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Cited by 323Cancer Immunotherapy and BiomarkersCancer Cells and MetastasisTGF-β signaling in diseases

Tumor microenvironment signaling and therapeutics in cancer progression

Open access
Goenka, Anshika, Khan, Fatima, Verma, Bhupender, Sinha, Priyanka, Dmello, Crismita C., Jogalekar, Manasi P., Gangadaran, Prakash, Ahn, Byeong‐Cheol·2023·Cancer Communications
DOI 10.1002/cac2.12416PMC PMC10174093
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Abstract

Tumor development and metastasis are facilitated by the complex interactions between cancer cells and their microenvironment, which comprises stromal cells and extracellular matrix (ECM) components, among other factors. Stromal cells can adopt new phenotypes to promote tumor cell invasion. A deep understanding of the signaling pathways involved in cell‐to‐cell and cell‐to‐ECM interactions is needed to design effective intervention strategies that might interrupt these interactions. In this review, we describe the tumor microenvironment (TME) components and associated therapeutics. We discuss the clinical advances in the prevalent and newly discovered signaling pathways in the TME, the immune checkpoints and immunosuppressive chemokines, and currently used inhibitors targeting these pathways. These include both intrinsic and non‐autonomous tumor cell signaling pathways in the TME: protein kinase C (PKC) signaling, Notch, and transforming growth factor (TGF‐β) signaling, Endoplasmic Reticulum (ER) stress response, lactate signaling, Metabolic reprogramming, cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) and Siglec signaling pathways. We also discuss the recent advances in Programmed Cell Death Protein 1 (PD‐1), Cytotoxic T‐Lymphocyte Associated Protein 4 (CTLA4), T‐cell immunoglobulin mucin‐3 (TIM‐3) and Lymphocyte Activating Gene 3 (LAG3) immune checkpoint inhibitors along with the C‐C chemokine receptor 4 (CCR4)‐ C‐C class chemokines 22 (CCL22)/ and 17 (CCL17), C‐C chemokine receptor type 2 (CCR2)‐ chemokine (C‐C motif) ligand 2 (CCL2), C‐C chemokine receptor type 5 (CCR5)‐ chemokine (C‐C motif) ligand 3 (CCL3) chemokine signaling axis in the TME. In addition, this review provides a holistic understanding of the TME as we discuss the three‐dimensional and microfluidic models of the TME, which are believed to recapitulate the original characteristics of the patient tumor and hence may be used as a platform to study new mechanisms and screen for various anti‐cancer therapies. We further discuss the systemic influences of gut microbiota in TME reprogramming and treatment response. Overall, this review provides a comprehensive analysis of the diverse and most critical signaling pathways in the TME, highlighting the associated newest and critical preclinical and clinical studies along with their underlying biology. We highlight the importance of the most recent technologies of microfluidics and lab‐on‐chip models for TME research and also present an overview of extrinsic factors, such as the inhabitant human microbiome, which have the potential to modulate TME biology and drug responses.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes the signaling pathways and cellular components of the tumor microenvironment (TME) and the therapeutics targeting them, spanning PKC, Notch, TGF-β, ER stress, lactate, metabolic reprogramming, cGAS-STING and Siglec signaling, immune checkpoints, and immunosuppressive chemokine axes. It also surveys 3D/microfluidic TME models and the role of gut microbiota in modulating TME biology and treatment response.

Key findings

  • The TME is now understood to be either tumor-supportive or tumor-suppressive depending on cancer stage and type, with CAFs, TAMs, MDSCs and Tregs generally promoting immunosuppression while NK cells and CD8+ Teff cells are anti-tumorigenic.
  • Several signaling pathways play context-dependent, biphasic roles: PKC isoforms can be tumor-promoting or tumor-suppressing (e.g., PKCα showed antitumor activity via TAM polarization; PKCβ promotes VEGF-driven angiogenesis), and TGF-β acts as a tumor suppressor early but promotes CAF activation, angiogenesis and immune suppression later.
  • Clinical translation has been uneven: Notch-targeting antibodies such as brontictuzumab and tarextumab were discontinued for low response rates, whereas PD-1/PD-L1 and CTLA4 blockade (e.g., nivolumab plus ipilimumab) boosted CD8+ T cell activation in malignant pleural mesothelioma patients, and atezolizumab or durvalumab combined with carboplatin plus etoposide improved survival in advanced SCLC.
  • The review reports that TCGA analysis found cGAS, STING, TBK-1 and IRF-3 significantly elevated in almost all cancer models, with STING expression negatively correlated with infiltrating immune cells and predicting poor prognosis.

Methods

  • Narrative review; the authors state they extensively discuss advances in intrinsic and non-autonomous TME signaling mechanisms and their therapeutics from preclinical and clinical perspectives, and assess tumor models and gut microbiome effects.
  • Evidence is drawn from cited preclinical studies, mouse models, and clinical trials, summarized in two tables: Table 1 (clinical trials targeting TME components such as ECM, immune cells, CAFs, endothelial cells) and Table 2 (anticancer signaling and immune checkpoint inhibitory molecules in clinical trials).
  • No primary data collection, systematic search strategy, or meta-analysis is described.

Limitations

  • The paper states that PKC translation is impeded by a lack of mechanistic insights and robust pathological markers; that Notch therapeutics failed clinically due to high cytotoxicity of pan-NOTCH inhibitors and low antibody-drug conjugate affinity; and that targeting TGF-β risks systemic effects on healthy tissues, requiring better mechanistic understanding and patient stratification by biomarkers.
  • The paper notes that how lactate targeting affects host anti-tumor immunity and synergizes with other immunotherapies remains unexplored, and that the role of systemic nutrient levels in shaping the TME metabolic environment is still elusive.
  • Evident from the text (not stated as a limitation by the authors): as a narrative review without a described systematic search or quality appraisal, the selection and weighting of cited studies is not transparent, and several cited findings rest on preclinical mouse models rather than human data.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1002/cac2.12416

Cites

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Claims the paper makes

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  • Premisecitation

    CAFs recruit and polarize immune cells such as macrophages, neutrophils, T cells and DCs to a pro-tumorigenic phenotype by secreting cytokines, chemokines, and effector molecules such as IL-6, IL-8, TGF-β, CXCL12, CCL2, SDF-1, VEGF, IDO and TDO2.

    “CAFs recruit and polarize immune cells such as macrophages, neutrophils, T cells and DCs to a pro‐tumorigenic phenotype by secreting several cytokines, chemokines, and other effector molecules such as Interleukin 6 (IL‐6), and 8 (IL‐8), TGF‐β, CXCL12, CCL2, SDF‐1, VEGF, Indoleamine‐pyrrole 2,3‐dioxygenase (IDO) and tryptophan 2,3‐dioxygenase (TDO2) [27].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • Premisecitation

    CAFs secrete growth factors such as FGF and CXCL12 to promote angiogenesis via VEGF, SDF-1 and TGF-ß signaling.

    “They secrete several growth factors, such as fibroblast growth factor (FGF) and C‐X‐C motif chemokine ligand 12 (CXCL12), to promote angiogenesis via the VEGF, stromal cell‐derived factor 1 (SDF‐1) and TGF‐ß signaling [25, 26].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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  • Premisecitation

    Downregulating paracrine signaling of fibroblasts, such as PDGF/PDGFR and HGF/MET signaling pathways, promotes chemosensitivity in CAFs.

    “Furthermore, downregulating the paracrine signaling of fibroblasts, such as the platelet‐derived growth factor (PDGF)/ PDGF receptor (PDGFR) signaling pathway and hepatocyte growth factor (HGF)/ mesenchymal‐epithelial transition factor (MET) signaling pathway, was shown to promote chemosensitivity in CAFs [29, 30].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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  • Premisecitation

    CAFs consist of several types of stromal cells that differ in their origin, functions, number, and phenotype.

    “However, recent studies indicated that CAFs consist of several types of stromal cells that differ in their origin, functions, number, and phenotype [21, 22, 23, 24].”
    Quote in the paperSubstantial claim0 of 4 sources checked
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  • Premisecitation

    Certain CAFs (Slit2+ and CD146+ CAFs) have anti-tumorigenic effects such as tumor suppression and increased tumor chemosensitivity.

    “However, certain CAFs (Slit Guidance Ligand 2 [Slit2]+ and cluster of differentiation 146 [CD146]+ CAFs) were shown to have anti‐tumorigenic effects such as tumor suppression and increased tumor chemosensitivity [28].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    Systemic administration of PEGPH20 reduces stromal hyaluronic acid, normalizes interstitial fluid pressures, re-expands the microvasculature and leads to tumor suppression in pancreatic ductal adenocarcinomas murine models.

    “Moreover, Provenzano et al. found that systemic administration of pegvorhyaluronidase alfa (PEGPH20), an enzyme against hyaluronic acid, reduced stromal hyaluronic acid, normalized interstitial fluid pressures, re‐expanded the microvasculature and led to tumor suppression in pancreatic ductal adenocarcinomas murine models [41].”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    Treg cells and MDSCs facilitate a pro-tumorigenic response in the TME and result in an immunosuppressive TME and therapy failure.

    “Other immune cells facilitating a pro‐tumorigenic response in the TME include the immunomodulatory regulatory T (Treg) cells and the myeloid suppressor (MDSCs) that result in an immunosuppressive TME [17] and therapy failure.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    ECM acts as a scaffold and plays a tumor-suppressing role in healthy tissues; however, it is modified in tumor tissue to possess a tumor-promoting role.

    “ECM acts as a scaffold and plays a tumor‐suppressing role in healthy tissues; however, it is modified in tumor tissue to possess a tumor‐promoting role [37].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Robertson C. The extracellular matrix in breast cancer predicts prognosis through composition, splicing, and crosslinking. Exp Cell Res. 2016; 343(1): 73– 81. 26597760 source

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    Premisecitation

    HIF-1α activation in tumor cells promotes secretion of proangiogenic factors such as VEGF, FGF-2, and PDGF, and stimulates angiogenesis.

    “Hypoxia‐inducible factor 1‐alpha (HIF‐1α) activation in tumor cells promotes the secretion of proangiogenic factors, such as VEGF, FGF‐2, and PDGF, and stimulates angiogenesis [32, 33].”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Premisecitation

    The presence of NK cells in the TME is believed to be anti-tumorigenic, resulting from release of cytokines and chemoattractants such as XCL1, CCL5 or FLT3LG and leading to APC accumulation in the TME.

    “However, the presence of NK cells in the TME is believed to be anti‐tumorigenic, resulting from the release of cytokines and chemoattractants such as X‐C motif chemokine ligand 1 (XCL1), chemokine ligand 5 (CCL5) or Fms‐related tyrosine kinase 3 ligand (FLT3LG) and leading to APC accumulation in the TME [18, 19, 20].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
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    Premisecitation

    ECM components underlying tumor-promoting activity, such as fibronectin and its splice variants, crosslinked collagen I and tenascin-C, are induced in the TME and interact with integrins to influence tumor cell migration, proliferation and cellular signaling.

    “The ECM components underlying tumor‐promoting activity, such as fibronectin and its splice variants, crosslinked collagen I and tenascin‐C, are induced in the TME [37, 38] and interact with integrins to influence tumor cell migration, proliferation and cellular signaling [39].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [37] Robertson C. The extracellular matrix in breast cancer predicts prognosis through composition, splicing, and crosslinking. Exp Cell Res. 2016; 343(1): 73– 81. 26597760 source

      Not checked in the free run.

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    Premisecitation

    Targeting VEGFA and ANGPT2 along with CD40 agonistic antibodies destroyed tumor fibrosis and induced T cell-mediated killing in chemoresistant and desmoplastic colorectal cancer cells.

    “Another study targeting chemoresistant and desmoplastic colorectal cancer (CRC) cells by targeting vascular endothelial growth factor A (VEGFA) and angiopoietin‐2 (ANGPT2) along with the cluster of differentiation 40 (CD40) agonistic antibodies destroyed tumor fibrosis and induced T cell‐mediated killing [7].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    Inhibition of PAK4, selectively expressed by tumor endothelial cells in glioma, re-sensitizes tumor cells to CAR-T cell therapy engineered against EGFRvIII mutation in glioma, allowing engineered T cells to enter the brain and elicit a robust immune response.

    “In one study, inhibition of p21‐activated kinase 4 (PAK4), selectively expressed by tumor endothelial cells (ECs) in glioma, re‐sensitizes tumor cells to chimeric antigen receptor (CAR)‐T cell therapy engineered against epidermal growth factor receptor variant III (EGFRvIII) mutation in glioma, allowing engineered T cells to enter the brain and elicit a robust immune response [6].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    Anti-angiogenic drugs promote vasoinvasion leading to metastasis and reduced lifespan in mice.

    “However, tumor cells become resistant after long‐term treatment, and these anti‐angiogenic drugs were shown to promote vasoinvasion leading to metastasis and reduced lifespan in mice [36].”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    The blood and lymphatic ECs, complex collagen fibers and glycoproteins form the ECM, while CAFs and mesenchymal stem cells assist in ECM remodeling and chemoresistance.

    “The blood and lymphatic ECs, complex collagen fibers and glycoproteins form the ECM, while the cancer‐associated fibroblasts (CAFs) and mesenchymal stem cells further assist in ECM remodeling and even chemoresistance [13, 14].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Premisecitation

    Anti-VEGF treatment is ineffective in obese mice due to increased IL-6 and FGF-2 expression by adipocytes in the TME, while co-targeting these improves anti-VEGF therapy response.

    “For example, anti‐VEGF treatment is ineffective in obese mice due to increased IL‐6 and FGF‐2 expression by the adipocytes in the TME, while co‐targeting these improve the anti‐VEGF therapy response [75].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] Incio J, Ligibel JA, McManus DT, Suboj P, Jung K, Kawaguchi K, et al. Obesity promotes resistance to anti‐VEGF therapy in breast cancer by up‐regulating IL‐6 and potentially FGF‐2. Sci Transl Med. 2018; 10(432): eaag0945. 29540614 PMC5936748 source

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    Premisecitation

    CAF depletion reduces infiltrating immune cells, leading to tumor progression.

    “However, CAF depletion has also been shown to reduce infiltrating immune cells, leading to tumor progression [100].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [100] Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF, Sastra SA, et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell. 2014; 25(6): 735– 47. 24856585 PMC4096698 source

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    Premisecitation

    Depleting FAP+ CAFs via a FAP vaccine decreases collagen density and improves chemoresistance in mouse models.

    “For example, depleting fibroblast activation protein (FAP)+ CAFs via a FAP vaccine decreases collagen density and improves chemoresistance in mouse models [99].”
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    Premisecitation

    A prodrug of DON that blocks glutamine metabolism in myeloid precursor cells can differentiate monocytes into anti-tumor TAMs, leading to tumor regression in mouse models.

    “Moreover, a prodrug of 6‐diazo‐5‐oxo‐l‐norleucine (DON) that blocks glutamine metabolism in myeloid precursor cells can differentiate monocytes into anti‐tumor TAMs, leading to tumor regression in mouse models [56].”
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    Premisecitation

    Immune checkpoint blockers pembrolizumab and nivolumab are among the most frequently used blockers, along with US FDA-approved PD-1/PD-L1 inhibitors.

    “Immune checkpoint blockers pembrolizumab and nivolumab are among the most frequently used blockers, along with US FDA‐approved PD‐1/PD‐L1 inhibitors [96].”
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    Premisecitation

    Most tumors are poorly vascularized and hypoxic, which advances cancer progression and chemoresistance.

    “However, most tumors are poorly vascularized and hypoxic, which advances cancer progression and chemoresistance [70, 71].”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Premisecitation

    Histone deacetylase inhibitor TMP195 polarizes TAMs toward an anti-tumor phenotype and increases the efficacy of carboplatin, paclitaxel, and anti-PD-1 therapies.

    “Histone deacetylase inhibitor, TMP195, polarizes TAMs toward an anti‐tumor phenotype and increases the efficacy of carboplatin, paclitaxel, and anti‐PD‐1 therapies [84].”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    These signaling pathways are crucial in maintaining a favorable TME and developing resistance against therapies or multi-drug resistance.

    “These signaling pathways are crucial in maintaining a favorable TME and developing resistance against therapies or multi‐drug resistance [109].”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    Breast cancer samples have remarkably high fibrillar collagen content, leading to a poor prognosis.

    “For example, breast cancer samples have a remarkably high fibrillar collagen content, leading to a poor prognosis [76, 77].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [76] Bourgot I, Primac I, Louis T, Noël A, Maquoi E. Reciprocal Interplay Between Fibrillar Collagens and Collagen‐Binding Integrins: Implications in Cancer Progression and Metastasis. Front Oncol. 2020; 10: 1488. 33014790 PMC7461916 source

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    Premisecitation

    Peptide-based vaccines that deliver long immunogenic antigens to DCs induce CD4+ T and CD8+ T cell cytotoxic activities and improve survival in patients with HPV-16-positive cervical cancer and newly diagnosed glioblastoma.

    “Also, peptide‐based vaccines that deliver long immunogenic antigens to DCs have been shown to induce CD4+ T and CD8+ T cell cytotoxic activities and improve survival in patients with HPV‐16‐positive cervical cancer and newly diagnosed glioblastoma (NCT02455557) [59].”
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    Premisecitation

    Targeting immunosuppressive TGF-β signaling in T cells by PLGA nanoparticles enhances antitumor immunity in mice; the nanoparticles bind to T cells and release TGF-βR1 inhibitor SD-208 that stimulates potency of CD8+ Teff cells while inhibiting Treg cells in the TME.

    “Targeting the immunosuppressive TGF‐β signaling in T cells by PLGA nanoparticles enhances antitumor immunity in mice. These nanoparticles bind to T cells and release a TGF‐βR1 inhibitor, SD‐208, that stimulates the potency of CD8+ Teff cells while inhibiting the inhibitory Treg cells in the TME [90].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90] Schmid D, Park CG, Hartl CA, Subedi N, Cartwright AN, Puerto RB, et al. T cell‐targeting nanoparticles focus delivery of immunotherapy to improve antitumor immunity. Nat Commun. 2017; 8(1): 1747. 29170511 PMC5700944 source

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    CAF depletion in the TME leads to a shift from Th2 to Th1 to promote inflammation, accompanied by up-regulation of IL-2 and IL-7 and downregulation of TAMs, Tregs and MDSCs.

    “CAF depletion in the TME leads to a shift from T helper 2 (Th2) to T helper 1 (Th1) to promote inflammation, accompanied by the up‐regulation of IL‐2 and IL‐7 and downregulation of TAMs, Tregs and MDSCs [101].”
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    • cites [101] Liao D, Luo Y, Markowitz D, Xiang R, Reisfeld RA. Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model. PLoS One. 2009; 4(11): e7965. 19956757 PMC2775953 source

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    Interpretationnone given

    The major shortcomings of Notch signaling therapeutics are high cytotoxicity shown by pan-NOTCH inhibitors and low affinity of antibody-drug conjugates.

    “The major shortcomings are high cytotoxicity, shown by pan‐NOTCH inhibitors, and low affinity of antibody‐drug conjugates (ADC).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Notch signaling plays a key role in determining cell fate and regulating embryonic as well as tumor angiogenesis.

    “Notch signaling plays a key role in determining cell fate and regulating embryonic as well as tumor angiogenesis [132, 133].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [132] Gale NW, Dominguez MG, Noguera I, Pan L, Hughes V, Valenzuela DM, et al. Haploinsufficiency of delta‐like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. Proc Nat Acad Sci USA. 2004; 101(45): 15949– 54. 15520367 PMC524697 source

      Not checked in the free run.

    • cites [133] Kofler NM, Shawber CJ, Kangsamaksin T, Reed HO, Galatioto J, Kitajewski J. Notch signaling in developmental and tumor angiogenesis. Genes Cancer. 2011; 2(12): 1106– 16. 22866202 PMC3411124 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Brontictuzumab and Tarextumab were tested in relapsed or refractory tumors, small-cell lung cancer and pancreatic ductal adenocarcinoma, but clinical trials were discontinued owing to a low response rate in patients.

    “Brontictuzumab (anti‐Notch1 receptor antibody) and Tarextumab (anti‐Notch2/3 receptor antibody) were tested in relapsed or refractory tumors, small‐cell lung cancer and pancreatic ductal adenocarcinoma, but clinical trials were discontinued owing to a low response rate in patients [145, 146, 147].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [145] Ferrarotto R, Eckhardt G, Patnaik A, LoRusso P, Faoro L, Heymach JV, et al. A phase I dose‐escalation and dose‐expansion study of brontictuzumab in subjects with selected solid tumors. Ann Oncol: Official Journal of the European Society for Medical Oncology. 2018; 29(7): 1561– 8. 29726923 source

      Not checked in the free run.

    • cites [146] Casulo C, Ruan J, Dang NH, Gore L, Diefenbach C, Beaven AW, et al. Safety and Preliminary Efficacy Results of a Phase I First‐in‐Human Study of the Novel Notch‐1 Targeting Antibody Brontictuzumab (OMP‐52M51) Administered Intravenously to Patients with Hematologic Malignancies. Blood. 2016; 128(22): 5108. source

      Not checked in the free run.

    • cites [147] Hu ZI, Bendell JC, Bullock A, LoConte NK, Hatoum H, Ritch P, et al. A randomized phase II trial of nab‐paclitaxel and gemcitabine with tarextumab or placebo in patients with untreated metastatic pancreatic cancer. Cancer Med. 2019; 8(11): 5148– 57. 31347292 PMC6718621 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Demcizumab and enoticumab alone or in combination with existing antitumor drugs, and Rovalpituzumab, have progressed to randomized phase II trials.

    “Demcizumab and enoticumab (Dll4 targeting antibodies) alone or in combination with existing antitumor drugs, and Rovalpituzumab (anti‐Dll3 targeting antibody) work by suppressing cancer stem cells and angiogenesis in the TME and have progressed to randomized phase II trials [142, 143, 144].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [142] McKeage MJ, Kotasek D, Markman B, Hidalgo M, Millward MJ, Jameson MB, et al. Phase IB Trial of the Anti‐Cancer Stem Cell DLL4‐Binding Agent Demcizumab with Pemetrexed and Carboplatin as First‐Line Treatment of Metastatic Non‐Squamous NSCLC. Target Oncol. 2018; 13(1): 89– 98. 29188408 source

      Not checked in the free run.

    • cites [143] Mayer RJ, Ohtsu A, Yoshino T, Falcone A, Garcia‐Carbonero R, Tabernero J, et al. TAS‐102 versus placebo plus best supportive care in patients with metastatic colorectal cancer refractory to standard therapies: Final survival results of the phase III RECOURSE trial. J Clin Oncol. 2016; 34(4_suppl): 634. source

      Not checked in the free run.

    • cites [144] Jimeno A, LoRusso P, Strother RM, Diamond JR, Plato L, Younger A, et al. Phase I study of REGN421 (R)/SAR153192, a fully‐human delta‐like ligand 4 (Dll4) monoclonal antibody (mAb), in patients with advanced solid tumors. J Clin Oncol. 2013; 31(15_suppl): 2502. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Demcizumab, enoticumab, and Rovalpituzumab suppress cancer stem cells and angiogenesis in the TME.

    “Demcizumab and enoticumab (Dll4 targeting antibodies) alone or in combination with existing antitumor drugs, and Rovalpituzumab (anti‐Dll3 targeting antibody) work by suppressing cancer stem cells and angiogenesis in the TME and have progressed to randomized phase II trials [142, 143, 144].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [142] McKeage MJ, Kotasek D, Markman B, Hidalgo M, Millward MJ, Jameson MB, et al. Phase IB Trial of the Anti‐Cancer Stem Cell DLL4‐Binding Agent Demcizumab with Pemetrexed and Carboplatin as First‐Line Treatment of Metastatic Non‐Squamous NSCLC. Target Oncol. 2018; 13(1): 89– 98. 29188408 source

      Not checked in the free run.

    • cites [143] Mayer RJ, Ohtsu A, Yoshino T, Falcone A, Garcia‐Carbonero R, Tabernero J, et al. TAS‐102 versus placebo plus best supportive care in patients with metastatic colorectal cancer refractory to standard therapies: Final survival results of the phase III RECOURSE trial. J Clin Oncol. 2016; 34(4_suppl): 634. source

      Not checked in the free run.

    • cites [144] Jimeno A, LoRusso P, Strother RM, Diamond JR, Plato L, Younger A, et al. Phase I study of REGN421 (R)/SAR153192, a fully‐human delta‐like ligand 4 (Dll4) monoclonal antibody (mAb), in patients with advanced solid tumors. J Clin Oncol. 2013; 31(15_suppl): 2502. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Small molecule and peptide inhibitors of the intracellular domain of the Notch receptor (NICD)-transcriptional complex assembly have been developed, and phase I/IIa clinical trials are being conducted on CB-103 (NCT03422679).

    “Small molecule and peptide inhibitors of the intracellular domain of the Notch receptor (NICD)‐transcriptional complex assembly have been developed, and phase I/IIa clinical trials are being conducted on one such inhibitor, CB‐103 (NCT03422679).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Epoxytiglianes, a class of PKC activators, showed efficacy in preclinical mouse models and clinical mast cell tumors in canine models.

    “Epoxytiglianes, another class of PKC activators, showed efficacy in preclinical mouse models and clinical mast cell tumors in canine models [126, 127, 128].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [126] Boyle GM, D'Souza MMA, Pierce CJ, Adams RA, Cantor AS, Johns JP, et al. Intra‐lesional injection of the novel PKC activator EBC‐46 rapidly ablates tumors in mouse models. PLoS One. 2014; 9(10): e108887. 25272271 PMC4182759 source

      Not checked in the free run.

    • cites [127] Miller J, Campbell J, Blum A, Reddell P, Gordon V, Schmidt P, et al. Dose Characterization of the Investigational Anticancer Drug Tigilanol Tiglate (EBC‐46) in the Local Treatment of Canine Mast Cell Tumors. Front vet sci. 2019; 6: 106. 31111038 PMC6499228 source

      Not checked in the free run.

    • cites [128] De Ridder TR, Campbell JE, Burke‐Schwarz C, Clegg D, Elliot EL, Geller S, et al. Randomized controlled clinical study evaluating the efficacy and safety of intratumoral treatment of canine mast cell tumors with tigilanol tiglate (EBC‐46). J Vet Intern Med. 2021; 35(1): 415– 29. 32542733 PMC7848366 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibiting γ-secretase using small molecules like PF-03084014 and BMS-906024 has shown promising results in triple-negative breast cancer, desmoid tumors and pancreatic ductal adenocarcinoma, and related phase II and III trials are currently underway.

    “Inhibiting γ‐secretase using small molecules like PF‐03084014 and BMS‐906024 has shown promising results in triple‐negative breast cancer, desmoid tumors and pancreatic ductal adenocarcinoma, and related phase II and III trials are currently underway [150, 151, 152, 153].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [150] Messersmith WA, Shapiro GI, Cleary JM, Jimeno A, Dasari A, Huang B, et al. A Phase I, dose‐finding study in patients with advanced solid malignancies of the oral γ‐secretase inhibitor PF‐03084014. Clin Cancer Res. 2015; 21(1): 60– 7. 25231399 source

      Not checked in the free run.

    • cites [151] Kummar S, O'Sullivan Coyne G, Do KT, Turkbey B, Meltzer PS, Polley E, et al. Clinical Activity of the γ‐Secretase Inhibitor PF‐03084014 in Adults With Desmoid Tumors (Aggressive Fibromatosis). J Clin Oncol. 2017; 35(14): 1561– 9. 28350521 PMC5455706 source

      Not checked in the free run.

    • cites [152] Papayannidis C, DeAngelo DJ, Stock W, Huang B, Shaik MN, Cesari R, et al. A Phase 1 study of the novel gamma‐secretase inhibitor PF‐03084014 in patients with T‐cell acute lymphoblastic leukemia and T‐cell lymphoblastic lymphoma. Blood Cancer J. 2015; 5(9): e350. 26407235 PMC4648526 source

      Not checked in the free run.

    • cites [153] Zweidler‐McKay PA, DeAngelo DJ, Douer D, Dombret H, Ottmann OG, Vey N, et al. The Safety and Activity of BMS‐906024, a Gamma Secretase Inhibitor (GSI) with Anti‐Notch Activity, in Patients with Relapsed T‐Cell Acute Lymphoblastic Leukemia (T‐ALL): Initial Results of a Phase 1 Trial. Blood. 2014; 124(21): 968. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Within the TME, PKC beta is a well-documented effector of VEGF signaling that promotes angiogenesis and is required for invasiveness in certain tumors, such as pancreatic tumors.

    “Moreover, within the TME, PKC beta, another PKC isoform, is a well‐documented effector of the VEGF signaling that promotes angiogenesis and is required for invasiveness in certain tumors, such as pancreatic tumors [122, 123, 124].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [122] Xia P, Aiello LP, Ishii H, Jiang ZY, Park DJ, Robinson GS, et al. Characterization of vascular endothelial growth factor's effect on the activation of protein kinase C, its isoforms, and endothelial cell growth. J Clin Invest. 1996; 98(9): 2018– 26. 8903320 PMC507645 source

      Not checked in the free run.

    • cites [123] Suzuma K, Takahara N, Suzuma I, Isshiki K, Ueki K, Leitges M, et al. Characterization of protein kinase C beta isoform's action on retinoblastoma protein phosphorylation, vascular endothelial growth factor‐induced endothelial cell proliferation, and retinal neovascularization. Proc Nat Acad Sci USA. 2002; 99(2): 721– 6. 11805327 PMC117372 source

      Not checked in the free run.

    • cites [124] Goicoechea SM, García‐Mata R, Staub J, Valdivia A, Sharek L, McCulloch CG, et al. Palladin promotes invasion of pancreatic cancer cells by enhancing invadopodia formation in cancer‐associated fibroblasts. Oncogene. 2014; 33(10): 1265– 73. 23524582 PMC3912215 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Phorbol esters, naturally occurring activating ligands of PKC, show tumor-promoting functions, suggesting PKC could be an oncogene.

    “Conversely, phorbol esters, the naturally occurring activating ligands of PKC, showed tumor‐promoting functions, suggesting that PKC could be an oncogene [111, 120, 121].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [111] Kikkawa U, Takai Y, Tanaka Y, Miyake R, Nishizuka Y. Protein kinase C as a possible receptor protein of tumor‐promoting phorbol esters. J Biol Chem. 1983; 258(19): 11442– 5. 6311812 source

      Not checked in the free run.

    • cites [120] Castagna M, Takai Y, Kaibuchi K, Sano K, Kikkawa U, Nishizuka Y. Direct activation of calcium‐activated, phospholipid‐dependent protein kinase by tumor‐promoting phorbol esters. J Biol Chem. 1982; 257(13): 7847– 51. 7085651 source

      Not checked in the free run.

    • cites [121] Griner EM, Kazanietz MG. Protein kinase C and other diacylglycerol effectors in cancer. Nat Rev Cancer. 2007; 7(4): 281– 94. 17384583 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    A distinct population within tumors can express distinct Notch ligands or paralogues, which can both activate and inhibit tumor development in different cancers because the outcome of Notch signaling is highly context-dependent.

    “Recent evidence indicates that a distinct population within tumors can express distinct Notch ligands or paralogues, which can both activate and inhibit tumor development in different cancers since the outcome of Notch signaling is highly changeable depending on the context.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Targeting TGF-β can systemically affect healthy tissues and tumor cells, causing safety concerns.

    “The pleiotropic effects of TGF‐β in tissue homeostasis have rendered exploiting their pro‐tumorigenic properties difficult, as targeting TGF‐β can systemically affect healthy tissues and tumor cells, thus safety concerns.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    High lactate concentration in the TME inhibits maturation of monocytes to dendritic cells and reduces cytokine production and cytotoxic activity by T cells and NK cells, contributing to suppressed immune recognition of cancer cells.

    “Additionally, high lactate concentration in the TME inhibits the maturation of monocytes to dendritic cells [203, 204] and reduces cytokine production and cytotoxic activity by T cells and NK cells [205, 206, 207], thereby contributing to suppressed immune recognition of cancer cells.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [203] Gottfried E, Kunz‐Schughart LA, Ebner S, Mueller‐Klieser W, Hoves S, Andreesen R, et al. Tumor‐derived lactic acid modulates dendritic cell activation and antigen expression. Blood. 2006; 107(5): 2013– 21. 16278308 source

      Not checked in the free run.

    • cites [204] Puig‐Kröger A, Pello OM, Muñiz‐Pello O, Selgas R, Criado G, Bajo M‐A, et al. Peritoneal dialysis solutions inhibit the differentiation and maturation of human monocyte‐derived dendritic cells: effect of lactate and glucose‐degradation products. J Leukocyte Biol. 2003; 73(4): 482– 92. 12660223 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Proton-coupled lactate efflux maintains an acidic phenotype in the TME, promoting angiogenesis, cell invasion and metastasis.

    “Recent reports suggest the role of proton‐coupled lactate efflux in maintaining an acidic phenotype in the TME, thereby promoting angiogenesis [197, 198], cell invasion [198] and metastasis [199, 200, 201, 202].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [197] Constant JS, Feng JJ, Zabel DD, Yuan H, Suh DY, Scheuenstuhl H, et al. Lactate elicits vascular endothelial growth factor from macrophages: a possible alternative to hypoxia. Wound Repair and Regeneration: Official Publication of the Wound Healing Society [and] the European Tissue Repair Society. 2000; 8(5): 353– 60. 11115148 source

      Not checked in the free run.

    • cites [198] Sun K, Tang S, Hou Y, Xi L, Chen Y, Yin J, et al. Oxidized ATM‐mediated glycolysis enhancement in breast cancer‐associated fibroblasts contributes to tumor invasion through lactate as metabolic coupling. EBioMedicine. 2019; 41: 370– 83. 30799198 PMC6442874 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tumor cells drive aerobic glycolysis and promote cell proliferation via fueling mitochondrial metabolism.

    “Regarding intrinsic metabolism, several studies have demonstrated that tumor cells drive aerobic glycolysis and promote cell proliferation via fueling mitochondrial metabolism [220, 221].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [220] Martinez‐Outschoorn UE, Pestell RG, Howell A, Tykocinski ML, Nagajyothi F, Machado FS, et al. Energy transfer in “parasitic” cancer metabolism: mitochondria are the powerhouse and Achilles' heel of tumor cells. Cell Cycle (Georgetown, Tex). 2011; 10(24): 4208– 16. 22033146 PMC3272257 source

      Not checked in the free run.

    • cites [221] DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 2008; 7(1): 11– 20. 18177721 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metabolic reprogramming, via regulating metabolic enzymes' activities, helps enrich the TME with nutrients and plays a causal role in tumor progression.

    “This reprogramming, via regulating metabolic enzymes’ activities, helps enrich the TME with nutrients and plays a causal role in tumor progression [217, 218].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [217] Lane AN, Higashi RM, Fan TW‐M. Metabolic reprogramming in tumors: Contributions of the tumor microenvironment. GENES DIS. 2020; 7(2): 185– 98. 32215288 PMC7083762 source

      Not checked in the free run.

    • cites [218] Xia L, Oyang L, Lin J, Tan S, Han Y, Wu N, et al. The cancer metabolic reprogramming and immune response. Mol Cancer. 2021; 20(1): 28. 33546704 PMC7863491 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    TGF-β is a family of cytokines that regulate embryonic development, tissue homeostasis and regeneration.

    “Transforming growth factor‐β (TGF‐β) is a family of cytokines that intricately regulate embryonic development, tissue homeostasis and regeneration [156].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [156] Chaudhury A, Howe PH. The tale of transforming growth factor‐beta (TGFbeta) signaling: a soigné enigma. IUBMB Life. 2009; 61(10): 929– 39. 19787707 PMC2810629 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cancer cells adapt to protective TGF-β signaling and utilize its moonlighting functions to create a conducive TME by activating CAFs, promoting angiogenesis and ECM production, and suppressing anti-tumor immune responses.

    “However, cancer cells adapt to the protective TGF‐β signaling and utilize its moonlighting functions to create a conducive TME by activating CAFs, promoting angiogenesis and ECM production, and suppressing anti‐tumor immune responses [160, 161, 162].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [160] Batlle E, Massagué J. Transforming Growth Factor‐β Signaling in Immunity and Cancer. Immunity. 2019; 50(4): 924– 40. 30995507 PMC7507121 source

      Not checked in the free run.

    • cites [161] Derynck R, Turley SJ, Akhurst RJ. TGFβ biology in cancer progression and immunotherapy. Nat Rev Clin Oncol. 2021; 18(1): 9– 34. 32710082 PMC9721352 source

      Not checked in the free run.

    • cites [162] Xie F, Ling L, van Dam H, Zhou F, Zhang L. TGF‐β signaling in cancer metastasis. Acta Biochim Biophy Sin. 2018; 50(1): 121– 32. 29190313 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PERK inhibitors GSK2606414 and GSK2656157 possess antitumor activity and can reactivate T cell function in the TME in mouse embryonic fibroblasts.

    “Similarly, PERK inhibitors GSK2606414 and GSK2656157 possess antitumor activity and can reactivate T cell function in the TME in mouse embryonic fibroblasts; however, these compounds had adverse effects in mouse models, hindering their progress toward clinical trials [190, 191, 192, 193].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [190] Hurst KE, Lawrence KA, Essman MT, Walton ZJ, Leddy LR, Thaxton JE. Endoplasmic Reticulum Stress Contributes to Mitochondrial Exhaustion of CD8+ T Cells. Cancer Immunol Res. 2019; 7(3): 476– 86. 30659052 PMC6397687 source

      Not checked in the free run.

    • cites [191] Atkins C, Liu Q, Minthorn E, Zhang S‐Y, Figueroa DJ, Moss K, et al. Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res. 2013; 73(6): 1993– 2002. 23333938 source

      Not checked in the free run.

    • cites [192] Rojas‐Rivera D, Delvaeye T, Roelandt R, Nerinckx W, Augustyns K, Vandenabeele P, et al. When PERK inhibitors turn out to be new potent RIPK1 inhibitors: critical issues on the specificity and use of GSK2606414 and GSK2656157. Cell Death Differ. 2017; 24(6): 1100– 10. 28452996 PMC5442476 source

      Not checked in the free run.

    • cites [193] Nie Z, Chen M, Wen X, Gao Y, Huang D, Cao H, et al. Endoplasmic Reticulum Stress and Tumor Microenvironment in Bladder Cancer: The Missing Link. Front Cell Dev Biol. 2021; 9: 683940. 34136492 PMC8201605 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TGF-β regulates adhesion, differentiation, cell cycle progression and apoptosis of cancer cells.

    “Moreover, they regulate various aspects of cancer cells, such as adhesion, differentiation, cell cycle progression and apoptosis [157, 158].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [157] Syed V. TGF‐β Signaling in Cancer. J Cell Biochem. 2016; 117(6): 1279– 87. 26774024 source

      Not checked in the free run.

    • cites [158] Katz LH, Li Y, Chen J‐S, Muñoz NM, Majumdar A, Chen J, et al. Targeting TGF‐β signaling in cancer. Expert Opin Ther Targets. 2013; 17(7): 743– 60. 23651053 PMC3745214 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reduction in mTOR activity diminishes IFNγ transcripts in T cells, mitigating Th1 CD4+ T cell differentiation.

    “Reduction in mTOR activity diminishes IFNγ transcripts in T cells, mitigating Th1 CD4+ T cell differentiation [227, 228, 229].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [227] Cham CM, Driessens G, O'Keefe JP, Gajewski TF. Glucose deprivation inhibits multiple key gene expression events and effector functions in CD8+ T cells. Eur J Immunol. 2008; 38(9): 2438– 50. 18792400 PMC3008428 source

      Not checked in the free run.

    • cites [228] Waickman AT, Powell JD. mTOR, metabolism, and the regulation of T‐cell differentiation and function. Immunol Rev. 2012; 249(1): 43– 58. 22889214 PMC3419491 source

      Not checked in the free run.

    • cites [229] Cham CM, Gajewski TF. Glucose availability regulates IFN‐gamma production and p70S6 kinase activation in CD8+ effector T cells. J Immunol (Baltimore, Md: 1950). 2005; 174(8): 4670– 7. 15814691 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Limiting glucose levels leads to cellular competition and impairs T-cell function via decreased mTOR signaling.

    “Limiting glucose levels leads to cellular competition; this impairs T‐cell function via decreased mTOR signaling.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [227] Cham CM, Driessens G, O'Keefe JP, Gajewski TF. Glucose deprivation inhibits multiple key gene expression events and effector functions in CD8+ T cells. Eur J Immunol. 2008; 38(9): 2438– 50. 18792400 PMC3008428 source

      Not checked in the free run.

    • cites [228] Waickman AT, Powell JD. mTOR, metabolism, and the regulation of T‐cell differentiation and function. Immunol Rev. 2012; 249(1): 43– 58. 22889214 PMC3419491 source

      Not checked in the free run.

    • cites [229] Cham CM, Gajewski TF. Glucose availability regulates IFN‐gamma production and p70S6 kinase activation in CD8+ effector T cells. J Immunol (Baltimore, Md: 1950). 2005; 174(8): 4670– 7. 15814691 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Targeting the tumor cells' proliferative profile also affects normal cell metabolism at the systemic level.

    “Targeting the tumor cells’ proliferative profile also affects normal cell metabolism at the systemic level.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    TCGA dataset analysis revealed that the STING expression level in cancer is negatively correlated with infiltrating immune cells in various tumor models, demonstrating that significant upregulation of the cGAS-STING signaling mechanism predicts a poor prognosis in cancer patients.

    “Moreover, TCGA dataset analysis revealed that the STING expression level in cancer is negatively correlated with infiltrating immune cells in various tumor models, demonstrating that significant upregulation of the cGAS‐STING signaling mechanism predicts a poor prognosis in cancer patients [252].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [252] An X, Zhu Y, Zheng T, Wang G, Zhang M, Li J, et al. An Analysis of the Expression and Association with Immune Cell Infiltration of the cGAS/STING Pathway in Pan‐Cancer. Mol Ther Nucleic Acids. 2019; 14: 80– 9. 30583098 PMC6305687 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The gut microbiome produces specific microbial metabolites that can be altered by dietary restrictions, thus affecting tumor cell metabolism.

    “Moreover, the gut microbiome also produces specific microbial metabolites that can be altered by dietary restrictions, thus affecting tumor cell metabolism [243].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [243] Cogdill AP, Gaudreau PO, Arora R, Gopalakrishnan V, Wargo JA. The Impact of Intratumoral and Gastrointestinal Microbiota on Systemic Cancer Therapy. Trends Immunol. 2018; 39(11): 900– 20. 30392721 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These enzymes perform their non-canonical functions via protein-protein interactions and regulate central signaling pathways and functions of several organelles, such as the nucleus, ER and mitochondria.

    “Interestingly, these enzymes perform their non‐canonical functions via protein‐protein interactions and regulate many central signaling pathways and functions of several organelles, such as the nucleus, ER and mitochondria [249].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [249] Sun Q, Chen X, Ma J, Peng H, Wang F, Zha X, et al. Mammalian target of rapamycin up‐regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth. Proc Nat Acad Sci USA. 2011; 108(10): 4129– 34. 21325052 PMC3054028 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Solid tumors show glutamine-depleted cores, which promote histone hypermethylation, resulting in reduced expression of differentiation-related genes and cancer cell dedifferentiation.

    “Furthermore, solid tumors, being metabolically heterogeneous, show glutamine‐depleted cores, which promote histone hypermethylation, resulting in the reduced expression of differentiation‐related genes and cancer cell dedifferentiation [238, 239].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [238] Pan M, Reid MA, Lowman XH, Kulkarni RP, Tran TQ, Liu X, et al. Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. Nat Cell Biol. 2016; 18(10): 1090– 101. 27617932 PMC5536113 source

      Not checked in the free run.

    • cites [239] Cluntun AA, Lukey MJ, Cerione RA, Locasale JW. Glutamine Metabolism in Cancer: Understanding the Heterogeneity. Trends Cancer. 2017; 3(3): 169– 80. 28393116 PMC5383348 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chromosomal instability induces chronic inflammatory signals by constantly activating the cGAS-STING signaling mechanism, which downstream NF-κB function and consecutively increases metastatic cancer cell progression.

    “Chromosomal instability induces chronic inflammatory signals by constantly activating the cGAS‐STING signaling mechanism, which downstream NF‐κB function and consecutively increases metastatic cancer cell progression [256] (Figure 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [256] Li J, Duran MA, Dhanota N, Chatila WK, Bettigole SE, Kwon J, et al. Metastasis and Immune Evasion from Extracellular cGAMP Hydrolysis. Cancer Discov. 2021; 11(5): 1212– 27. 33372007 PMC8102348 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The four genes MB21D1, TMEM173, TBK1 and IRF3 were significantly elevated in almost all cancer models, suggesting that cGAS-STING signal transduction might be stimulated in all cancer types.

    “Comprehensive research and recent evidence proved that these four genes were significantly elevated in almost all cancer models, suggesting that cGAS‐STING signal transduction might be stimulated in all cancer types [252, 253].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [252] An X, Zhu Y, Zheng T, Wang G, Zhang M, Li J, et al. An Analysis of the Expression and Association with Immune Cell Infiltration of the cGAS/STING Pathway in Pan‐Cancer. Mol Ther Nucleic Acids. 2019; 14: 80– 9. 30583098 PMC6305687 source

      Not checked in the free run.

    • cites [253] Bakhoum SF, Ngo B, Laughney AM, Cavallo J‐A, Murphy CJ, Ly P, et al. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature. 2018; 553(7689): 467– 72. 29342134 PMC5785464 source

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  • May combine two claims.

    Premisecitation

    NF-κB promotes the development of inflammation, tumors and immune dysfunction.

    “Additionally, NF‐κB promotes the development of inflammation, tumors and immune dysfunction [255].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [255] Decout A, Katz JD, Venkatraman S, Ablasser A. The cGAS‐STING pathway as a therapeutic target in inflammatory diseases. Nat Rev Immunol. 2021; 21(9): 548– 69. 33833439 PMC8029610 source

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  • May combine two claims.

    Premisecitation

    Glucose tracing studies indicate that tumor cells in highly perfused locations rely mainly on glucose, whereas those in less perfused regions depend on other carbon sources.

    “Glucose tracing studies stipulate that tumor cells in highly perfused locations rely mainly on glucose, whereas those in less perfused regions depend on other carbon sources [237].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [237] Hensley CT, Faubert B, Yuan Q, Lev‐Cohain N, Jin E, Kim J, et al. Metabolic Heterogeneity in Human Lung Tumors. Cell. 2016; 164(4): 681– 94. 26853473 PMC4752889 source

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  • May combine two claims.

    Premisecitation

    Glycolytic tumors have very low T cell infiltration and proliferation as activated T cells and tumor cells compete for glucose in the TME.

    “However, glycolytic tumors have very low T cell infiltration and proliferation as activated T cells and tumor cells compete for glucose in the TME [226].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [226] Yin Z, Bai L, Li W, Zeng T, Tian H, Cui J. Targeting T cell metabolism in the tumor microenvironment: an anti‐cancer therapeutic strategy. J Exp Clin Cancer Res. 2019; 38(1): 403. 31519198 PMC6743108 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dietary restrictions and hormonal modulation affect local metabolism.

    “Recent studies indicate that dietary restrictions and hormonal modulation affect local metabolism [240].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [240] Lien EC, Vander Heiden MG. A framework for examining how diet impacts tumour metabolism. Nat Rev Cancer. 2019; 19(11): 651– 61. 31530936 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    NF-κB regulates cell proliferation, apoptosis and survival of normal cells, thus acting as a crucial stimulator of the inflammatory response.

    “NF‐κB regulates cell proliferation, apoptosis and survival of normal cells, thus acting as a crucial stimulator of the inflammatory response.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [255] Decout A, Katz JD, Venkatraman S, Ablasser A. The cGAS‐STING pathway as a therapeutic target in inflammatory diseases. Nat Rev Immunol. 2021; 21(9): 548– 69. 33833439 PMC8029610 source

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  • May combine two claims.

    Premisecitation

    Glutamine is required for T-cell function and differentiation, and tumor cells use glutamine to activate STAT3 to promote cell proliferation.

    “For example, glutamine is required for T‐cell function and differentiation, and tumor cells use glutamine to activate STAT3 to promote cell proliferation [231].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [231] Cacace A, Sboarina M, Vazeille T, Sonveaux P. Glutamine activates STAT3 to control cancer cell proliferation independently of glutamine metabolism. Oncogene. 2017; 36(15): 2074– 84. 27748760 PMC5245769 source

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  • May combine two claims.

    Premisecitation

    In the TME, exhausted T cells exhibit reduced effector function and increased expression of immune checkpoints such as PD-1, CTLA4, TIM-3, LAG3 and BTLA.

    “In the TME, exhausted T cells exhibit reduced effector function and increased expression of immune checkpoints (e.g., PD‐1, CTLA4, TIM‐3, LAG3, BTLA) [269].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [269] Pang L, Khan F, Dunterman M, Chen P. Pharmacological targeting of the tumor‐immune symbiosis in glioblastoma. Trends Pharmacol Sci. 2022; 43(8): 686– 700. 35534356 PMC9288491 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CTLA4 binds to CD80 or CD86 with higher binding affinity and impedes CD28 co-stimulation.

    “CTLA4 binds to CD80 or CD86 with higher binding affinity and impedes CD28 co‐stimulation [295, 296].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [295] van der Merwe PA, Bodian DL, Daenke S, Linsley P, Davis SJ. CD80 (B7‐1) binds both CD28 and CTLA‐4 with a low affinity and very fast kinetics. J Exp Med. 1997; 185(3): 393– 403. 9053440 PMC2196039 source

      Not checked in the free run.

    • cites [296] Halliday N, Williams C, Kennedy A, Waters E, Pesenacker AM, Soskic B, et al. CD86 Is a Selective CD28 Ligand Supporting FoxP3+ Regulatory T Cell Homeostasis in the Presence of High Levels of CTLA‐4. Front Immunol. 2020; 11: 600000. 33363541 PMC7753196 source

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  • May combine two claims.

    Premisecitation

    Sialoglycans form different ligands for Factor H to evade complement activation and are proposed as a mediator of selectin-independent adhesion of lymphocyte trafficking, playing an essential role in metastasis.

    “Sialoglycans form different ligands for sialic acid binding proteins, i.e., Factor H (FH), to evade complemented activation and are proposed as a mediator of the selectin‐independent adhesion of lymphocyte trafficking, plays an essential role in metastasis [258, 264, 265].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [258] Varki A, Schnaar RL, Schauer R. Sialic Acids and Other Nonulosonic Acids. In: Varki A, Cummings RD, Esko JD, Stanley P, Hart GW, Aebi M, et al., editors. Essentials of Glycobiology. 3rd ed. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2015. 28876847

      Not checked in the free run.

    • cites [264] Büll C, Stoel MA, den Brok MH, Adema GJ. Sialic acids sweeten a tumor's life. Cancer Res. 2014; 74(12): 3199– 204. 24830719 source

      Not checked in the free run.

    • cites [265] Moore SR, Menon SS, Cortes C, Ferreira VP. Hijacking Factor H for Complement Immune Evasion. Front Immunol. 2021; 12: 602277. 33717083 PMC7947212 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PD-L1 or PD-L2 are expressed on the surface of cancer cells or antigen-presenting cells and transduce a signal for cooperation with PD-1 expression on the cell surface of T lymphocytes to stimulate restraint signaling.

    “Typically, PD‐L1 or PD‐L2 are expressed on the surface of cancer cells or antigen‐presenting cells and transduce a signal for cooperation with PD‐1 expression on the cell surface of T lymphocytes to stimulate restraint signaling [272, 273].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [272] Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol. 2020; 20(11): 651– 68. 32433532 PMC7238960 source

      Not checked in the free run.

    • cites [273] Hudson K, Cross N, Jordan‐Mahy N, Leyland R. The Extrinsic and Intrinsic Roles of PD‐L1 and Its Receptor PD‐1: Implications for Immunotherapy Treatment. Front Immunol. 2020; 11: 568931. 33193345 PMC7609400 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Studies over the past decades have suggested a clear function of sialoglycans in tumors via immune evasion, not only by shielding of antigens but also by sialic acids showing robust immunomodulatory properties as sugar moieties.

    “Studies over the past decades have suggested a clear function of sialoglycans in tumors via immune evasion, not only by shielding of antigens but also by sialic acids show robust immunomodulatory properties as sugar moieties [260, 262, 263].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [260] Büll C, den Brok MH, Adema GJ. Sweet escape: sialic acids in tumor immune evasion. Biochim Biophys Acta. 2014; 1846(1): 238– 46. 25026312 source

      Not checked in the free run.

    • cites [262] RodrÍguez E, Schetters STT, van Kooyk Y. The tumour glyco‐code as a novel immune checkpoint for immunotherapy. Nat Rev Immunol. 2018; 18(3): 204– 11. 29398707 source

      Not checked in the free run.

    • cites [263] Pearce OMT, Läubli H. Sialic acids in cancer biology and immunity. Glycobiology. 2016; 26(2): 111– 28. 26518624 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tumor cells secrete extracellular vesicles having membrane-bound PD-L1, mostly to upregulate the PD-1 mechanism, thus decreasing T lymphocytes.

    “Tumor cells secrete extracellular vesicles (EVs) having membrane‐bound PD‐L1, mostly to upregulate the PD‐1 mechanism, thus decreasing T lymphocytes [274, 275].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [274] Zhou K, Guo S, Li F, Sun Q, Liang G. Exosomal PD‐L1: New Insights Into Tumor Immune Escape Mechanisms and Therapeutic Strategies. Front Cell Dev Biol. 2020; 8: 569219. 33178688 PMC7593554 source

      Not checked in the free run.

    • cites [275] Liu J, Peng X, Yang S, Li X, Huang M, Wei S, et al. Extracellular vesicle PD‐L1 in reshaping tumor immune microenvironment: biological function and potential therapy strategies. Cell Commun Signal: CCS. 2022; 20(1): 14. 35090497 PMC8796536 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CD73high macrophages are immunosuppressive cells and have a signature distinct from microglia that persist after anti-PD-1 treatment.

    “In addition to PD‐L1+ TAMs, CyTOF and scRNA‐seq analyses revealed that CD73high macrophages are immunosuppressive cells and have a signature distinct from microglia that persist after anti‐PD‐1 treatment [269, 290, 291].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [269] Pang L, Khan F, Dunterman M, Chen P. Pharmacological targeting of the tumor‐immune symbiosis in glioblastoma. Trends Pharmacol Sci. 2022; 43(8): 686– 700. 35534356 PMC9288491 source

      Not checked in the free run.

    • cites [290] Goswami S, Walle T, Cornish AE, Basu S, Anandhan S, Fernandez I, et al. Immune profiling of human tumors identifies CD73 as a combinatorial target in glioblastoma. Nat Med. 2020; 26(1): 39– 46. 31873309 PMC7182038 source

      Not checked in the free run.

    • cites [291] Pang L, Khan F, Heimberger AB, Chen P. Mechanism and therapeutic potential of tumor‐immune symbiosis in glioblastoma. Trends Cancer. 2022; 8(10): 839– 54. 35624002 PMC9492629 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some tumors express PD-L1, which contributes to immune evasion by inhibiting cytotoxic responses.

    “Some tumors express PD‐L1, which contributes to immune evasion by inhibiting cytotoxic responses.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [270] Takehara T, Wakamatsu E, Machiyama H, Nishi W, Emoto K, Azuma M, et al. PD‐L2 suppresses T cell signaling via coinhibitory microcluster formation and SHP2 phosphatase recruitment. Commun Biol. 2021; 4(1): 581. 33990697 PMC8121797 source

      Not checked in the free run.

    • cites [271] Pawelczyk K, Piotrowska A, Ciesielska U, Jablonska K, Gletzel‐Plucinska N, Grzegrzolka J, et al. Role of PD‐L1 Expression in Non‐Small Cell Lung Cancer and Their Prognostic Significance according to Clinicopathological Factors and Diagnostic Markers. Int J Mol Sci. 2019; 20(4): 824. 30769852 PMC6413136 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    On tumor cells, sialoglycans are involved in tumor cell-to-cell interactions within the TME, and sialoglycans with negatively charged moieties could form an invisible cover by protecting tumor cells from immune recognition.

    “On tumor cells, sialoglycans are involved in tumor cell‐to‐cell interactions within the TME, and it was also suggested that sialoglycans with negatively charged moieties could form an invisible cover by protecting tumor cells from immune recognition [260].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [260] Büll C, den Brok MH, Adema GJ. Sweet escape: sialic acids in tumor immune evasion. Biochim Biophys Acta. 2014; 1846(1): 238– 46. 25026312 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The immuno-suppressive functions of immune checkpoints usually rely upon ligand-receptor interaction.

    “The immuno‐suppressive functions of the immune checkpoints usually rely upon ligand‐receptor interaction.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The CTLA4 cytoplasmic domain recruits SHP2 and contains YVKM motifs, which are considered to recruit SHP2.

    “It is commonly known that the CTLA4 cytoplasmic domain recruits SHP2 and contains YVKM motifs, which are considered to recruit SHP2 [298].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [298] Chikuma S, Kanamori M, Mise‐Omata S, Yoshimura A. Suppressors of cytokine signaling: Potential immune checkpoint molecules for cancer immunotherapy. Cancer Sci. 2017; 108(4): 574– 80. 28188673 PMC5406529 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    As paracrine signals, these factors further activate the NF-κB and STAT-1 pathway in metastatic brain cells, thus promoting brain metastasis and resistance in lung and breast cancer therapy.

    “Similarly, as paracrine signals, these factors further activate the NF‐κB and STAT‐1 pathway in metastatic brain cells, thus promoting brain metastasis and resistance in lung and breast cancer therapy [257].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [257] Chen Q, Boire A, Jin X, Valiente M, Er EE, Lopez‐Soto A, et al. Carcinoma‐astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature. 2016; 533(7604): 493– 8. 27225120 PMC5021195 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PD-L1 can interact in cis with CD80 to PD-1, which may disturb the PD-L1 and PD-1 interaction and the CTLA4 and CD80 interaction and also maintain the flexibility of CD80 to trigger CD28 signaling.

    “Additionally, PD‐L1 can interact in cis with Cluster of differentiation 80 (CD80) to PD‐1 [276, 277, 278], which may disturb the PD‐L1 and PD‐1 interaction and the CTLA4 and CD80 interaction and also maintain the flexibility of CD80 to trigger the signaling of CD28 [277, 279].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [276] Peng Q, Qiu X, Zhang Z, Zhang S, Zhang Y, Liang Y, et al. PD‐L1 on dendritic cells attenuates T cell activation and regulates response to immune checkpoint blockade. Nat Commun. 2020; 11(1): 4835. 32973173 PMC7518441 source

      Not checked in the free run.

    • cites [277] Zhao Y, Lee CK, Lin C‐H, Gassen RB, Xu X, Huang Z, et al. PD‐L1:CD80 Cis‐Heterodimer Triggers the Co‐stimulatory Receptor CD28 While Repressing the Inhibitory PD‐1 and CTLA‐4 Pathways. Immunity. 2019; 51(6): 1059– 73.e9. 31757674 PMC6935268 source

      Not checked in the free run.

    • cites [278] Sugiura D, Maruhashi T, Okazaki I‐M, Shimizu K, Maeda TK, Takemoto T, et al. Restriction of PD‐1 function by cis‐PD‐L1/CD80 interactions is required for optimal T cell responses. Science (New York, NY). 2019; 364(6440): 558– 66. 31000591 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The TME promotes abnormal sialylation in tumor cells and modulates the expression of siglec on infiltrating immune cells.

    “TME also promotes abnormal sialylation in tumor cells and modulates the expression of siglec on infiltrating immune cells [268].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [268] Jiang K‐Y, Qi L‐L, Kang F‐B, Wang L. The intriguing roles of Siglec family members in the tumor microenvironment. Biomark Res. 2022; 10(1): 22. 35418152 PMC9008986 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CTLA4 blockade within the TME could decrease the activation threshold of T cells while selectively depleting immunosuppressive regulatory T cells, which can increase the number of tumor-specific CD8+ T cells.

    “New studies suggest that CTLA4 blockade within the TME could decrease the activation threshold of T cells while selectively depleting immunosuppressive regulatory T cells, which can increase the number of tumor‐specific CD8+ T cells [294].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [294] Ha D, Tanaka A, Kibayashi T, Tanemura A, Sugiyama D, Wing JB, et al. Differential control of human Treg and effector T cells in tumor immunity by Fc‐engineered anti‐CTLA‐4 antibody. Proc Nat Acad Sci USA. 2019; 116(2): 609– 18. 30587582 PMC6329979 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LAG3 highly expressed on tumor-infiltrating lymphocytes interacts with tumor cell surface ligands to cause T cell dysfunction or exhaustion, promoting tumor immune escape, particularly in CD8+ T cells.

    “LAG3, highly expressed on the tumor‐infiltrating lymphocytes (TILs), interacts with ligands located on the surface of tumor cells to cause T cell dysfunction or even exhaustion, promoting tumor immune escape, particularly evident in CD8+ T cells [329, 330].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [329] Baitsch L, Baumgaertner P, Devêvre E, Raghav SK, Legat A, Barba L, et al. Exhaustion of tumor‐specific CD8⁺ T cells in metastases from melanoma patients. J Clin Invest. 2011; 121(6): 2350– 60. 21555851 PMC3104769 source

      Not checked in the free run.

    • cites [330] Matsuzaki J, Gnjatic S, Mhawech‐Fauceglia P, Beck A, Miller A, Tsuji T, et al. Tumor‐infiltrating NY‐ESO‐1‐specific CD8+ T cells are negatively regulated by LAG‐3 and PD‐1 in human ovarian cancer. Proc Nat Acad Sci USA. 2010; 107(17): 7875– 80. 20385810 PMC2867907 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Evidence confirms no immediate interaction between CTLA4 and SHP2, but it is perhaps arbitrated through the PI3K protein.

    “Evidence also confirms no immediate interaction between CTLA4 and SHP2. However, it is perhaps arbitrated through the PI3K protein [301].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [301] Schneider H, Rudd CE. Tyrosine phosphatase SHP‐2 binding to CTLA‐4: absence of direct YVKM/YFIP motif recognition. Biochem Biophys Res Commun. 2000; 269(1): 279– 83. 10694513 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some studies reported that there might be phosphotyrosine-independent cooperation among SHP2 and CTLA4 as alternated tyrosine CTLA4 could interact with SHP2 and inhibit TCRζ signaling pathways.

    “Some studies reported that there might be phosphotyrosine‐independent cooperation among SHP2 and CTLA4 as alternated tyrosine CTLA4 could interact with SHP2 and inhibit TCRζ signaling pathways [299, 300].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [299] Bagchi S, Yuan R, Engleman EG. Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance. Annual Review of Pathology. 2021; 16: 223– 49. 33197221 source

      Not checked in the free run.

    • cites [300] Miyatake S, Nakaseko C, Umemori H, Yamamoto T, Saito T. Src family tyrosine kinases associate with and phosphorylate CTLA‐4 (CD152). Biochem Biophys Res Commun. 1998; 249(2): 444– 8. 9712716 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LAG3 reduces T-cell count but does not necessarily induce apoptosis in T cells.

    “The essential role of LAG3 is to reduce the T‐cell counter, but it does not necessarily induce any apoptosis in T cells [322, 323].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [322] Hannier S, Tournier M, Bismuth G, Triebel F. CD3/TCR complex‐associated lymphocyte activation gene‐3 molecules inhibit CD3/TCR signaling. J Immunol (Baltimore, Md: 1950). 1998; 161(8): 4058– 65. 9780176 source

      Not checked in the free run.

    • cites [323] Castro‐Sanchez P, Teagle AR, Prade S, Zamoyska R. Modulation of TCR Signaling by Tyrosine Phosphatases: From Autoimmunity to Immunotherapy. Front Cell Dev Biol. 2020; 8: 608747. 33425916 PMC7793860 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    TIM-3 expression has a complex biology that negatively affects the immune system.

    “TIM‐3 expression has a “complex biology” that negatively affects the immune system.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The binding state of TIM-3 with ligands activates the phosphorylation of Tyr256 and Tyr263 tyrosine residues by IL-2-inducible T cell kinase (ITK), followed by ligand binding, releasing BAT3 into the cytoplasm.

    “The binding state of TIM‐3 with ligands activates the phosphorylation of Tyr256 and Tyr263 tyrosine residues by IL‐2‐inducible T cell kinase (ITK), followed by ligand binding, releasing BAT3 into the cytoplasm [310, 311].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [310] van de Weyer PS, Muehlfeit M, Klose C, Bonventre JV, Walz G, Kuehn EW. A highly conserved tyrosine of Tim‐3 is phosphorylated upon stimulation by its ligand galectin‐9. Biochem Biophys Res Commun. 2006; 351(2): 571– 6. 17069754 source

      Not checked in the free run.

    • cites [311] Das M, Zhu C, Kuchroo VK. Tim‐3 and its role in regulating anti‐tumor immunity. Immunol Rev. 2017; 276(1): 97– 111. 28258697 PMC5512889 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CTLA4 disrupted ZAP70 cluster formation in most T cells, although 5%-10% of T cells demonstrated cluster forming followed by anti-CD3 treatment.

    “CTLA4 disrupted the ZAP70 cluster formation in most T cells, although 5%‐10% of T cells demonstrated cluster forming followed by anti‐CD3 treatment [302, 303, 304].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [302] Schneider H, Smith X, Liu H, Bismuth G, Rudd CE. CTLA‐4 disrupts ZAP70 microcluster formation with reduced T cell/APC dwell times and calcium mobilization. Eur J Immunol. 2008; 38(1): 40– 7. 18095376 PMC5580795 source

      Not checked in the free run.

    • cites [303] Li K, Yuan Z, Lyu J, Ahn E, Davis SJ, Ahmed R, et al. PD‐1 suppresses TCR‐CD8 cooperativity during T‐cell antigen recognition. Nat Commun. 2021; 12(1): 2746. 33980853 PMC8115078 source

      Not checked in the free run.

    • cites [304] Liu H, Purbhoo MA, Davis DM, Rudd CE. SH2 domain containing leukocyte phosphoprotein of 76‐kDa (SLP‐76) feedback regulation of ZAP‐70 microclustering. Proc Nat Acad Sci USA. 2010; 107(22): 10166– 71. 20534575 PMC2890474 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LAG3 activates DC maturation and stimulation via regulation of intracellular phosphorylation proteins and promotes TNF-α.

    “LAG3 can activate the maturation and stimulation of DCs through the regulation of intracellular phosphorylation protein and promote chemokines like tumor necrosis factor α (TNF‐α) [328].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [328] Gandhi MK, Lambley E, Duraiswamy J, Dua U, Smith C, Elliott S, et al. Expression of LAG‐3 by tumor‐infiltrating lymphocytes is coincident with the suppression of latent membrane antigen‐specific CD8+ T‐cell function in Hodgkin lymphoma patients. Blood. 2006; 108(7): 2280– 9. 16757686 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LAG3 may synergize with PD-1 and CTLA4 to improve Treg inhibitory activity, leading to APC-induced immune tolerance.

    “LAG3 may synergize with other inhibitory molecules (PD‐1, CTLA4) to improve the inhibitory activity of Treg cells, leading to APC‐induced immune tolerance [327].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [327] Liang B, Workman C, Lee J, Chew C, Dale BM, Colonna L, et al. Regulatory T cells inhibit dendritic cells by lymphocyte activation gene‐3 engagement of MHC class II. J Immunol (Baltimore, Md: 1950). 2008; 180(9): 5916– 26. 18424711 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Release of BAT3 suggests that FYN tyrosine-protein kinase links with the TIM-3 cytoplasmic tail to generate inhibitory signaling that causes anergy of T cells by activating PAG1, prompting recruitment of CSK, leading to phosphorylating LCK and suppressing T cells.

    “Release of BAT3 suggests that FYN tyrosine‐protein kinase links with the TIM‐3 cytoplasmic tail to generate inhibitory signaling that causes anergy of T cells by activating the transmembrane protein phosphoprotein membrane anchor with glycosphingolipid microdomains 1 (PAG1). This prompts the recruitment of tyrosine kinase (CSK), leading to phosphorylating LCK and suppressing T cells [308, 312].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [308] Rangachari M, Zhu C, Sakuishi K, Xiao S, Karman J, Chen A, et al. Bat3 promotes T cell responses and autoimmunity by repressing Tim‐3–mediated cell death and exhaustion. Nat Med. 2012; 18(9): 1394– 400. 22863785 PMC3491118 source

      Not checked in the free run.

    • cites [312] Zhu C, Dixon KO, Newcomer K, Gu G, Xiao S, Zaghouani S, et al. Tim‐3 adaptor protein Bat3 is a molecular checkpoint of T cell terminal differentiation and exhaustion. Sci Adv. 2021; 7(18): eabd2710. 33931442 PMC8087420 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LAG3 positively induces Treg cell activation and stimulates their immunosuppressive function.

    “However, LAG3 can positively induce Treg cell activation and stimulate its immunosuppressive function [325, 326].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [325] Okamura T, Yamamoto K, Fujio K. Early Growth Response Gene 2‐Expressing CD4+LAG3+ Regulatory T Cells: The Therapeutic Potential for Treating Autoimmune Diseases. Front Immunol. 2018; 9: 340. 29535721 PMC5834469 source

      Not checked in the free run.

    • cites [326] Camisaschi C, Casati C, Rini F, Perego M, De Filippo A, Triebel F, et al. LAG‐3 expression defines a subset of CD4(+)CD25(high)Foxp3(+) regulatory T cells that are expanded at tumor sites. J Immunol (Baltimore, Md: 1950). 2010; 184(11): 6545– 51. 20421648 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BTLA contains ITIM and ITSM motifs and inhibits Grb2 protein in its cytoplasmic domain.

    “BTLA contains ITIM and ITSM motifs and stimulates the inhibition of Grb2 protein in its cytoplasmic domain.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [332] Gavrieli M, Murphy KM. Association of Grb‐2 and PI3K p85 with phosphotyrosile peptides derived from BTLA. Biochem Biophys Res Commun. 2006; 345(4): 1440– 5. 16725108 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BTLA is an essential co-signaling immune checkpoint protein with bidirectional functions.

    “BTLA is the essential co‐signaling immune checkpoint protein with bidirectional functions [331].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [331] Watanabe N, Gavrieli M, Sedy JR, Yang J, Fallarino F, Loftin SK, et al. BTLA is a lymphocyte inhibitory receptor with similarities to CTLA‐4 and PD‐1. Nat Immunol. 2003; 4(7): 670– 9. 12796776 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BTLA recruits SHP1 to abrogate CD28 and TCR signaling, whereas PD-1 recruits SHP2.

    “BTLA compels the strongest phosphatase SHP1 to abrogate the CD28 and TCR signaling mechanisms. In contrast, PD‐1 signaling recruits the weakened phosphatase SHP2 [282].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [282] Celis‐Gutierrez J, Blattmann P, Zhai Y, Jarmuzynski N, Ruminski K, Grégoire C, et al. Quantitative Interactomics in Primary T Cells Provides a Rationale for Concomitant PD‐1 and BTLA Coinhibitor Blockade in Cancer Immunotherapy. Cell Rep. 2019; 27(11): 3315– 30.e7. 31189114 PMC6581740 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BTLA and HVEM share ligand on CD8+ T cells, and their interaction suppresses T cell function.

    “In addition, BTLA and herpesvirus entry mediator (HVEM) shares ligand on the same T lymphocytes (CD8+), and the same cell interaction happens, which suppresses T cell function [333].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [333] Steinberg MW, Huang Y, Wang‐Zhu Y, Ware CF, Cheroutre H, Kronenberg M. BTLA interaction with HVEM expressed on CD8(+) T cells promotes survival and memory generation in response to a bacterial infection. PLoS One. 2013; 8(10): e77992. 24205057 PMC3813523 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CCL17 acts as a ligand for CCR4 and is produced by DCs or endothelial cells.

    “CCL17 acts as a ligand for CCR4 and is produced by DCs or endothelial cells [354, 355].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [354] Maruyama T, Kono K, Izawa S, Mizukami Y, Kawaguchi Y, Mimura K, et al. CCL17 and CCL22 chemokines within tumor microenvironment are related to infiltration of regulatory T cells in esophageal squamous cell carcinoma. Dis Esophagus. 2010; 23(5): 422– 9. 20002703

      Not checked in the free run.

    • cites [355] Mizukami Y, Kono K, Kawaguchi Y, Akaike H, Kamimura K, Sugai H, et al. CCL17 and CCL22 chemokines within tumor microenvironment are related to accumulation of Foxp3+ regulatory T cells in gastric cancer. Int J Cancer. 2008; 122(10): 2286– 93. 18224687 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Small molecules have potential as immune checkpoint inhibitors with nanomolar binding affinity to PD-L1, abolishing PD-1/PD-L1 interactions, improving T-cell activity, and enhancing antitumor immunity in colon, breast, pancreatic, and kidney cancer models.

    “Conceivable data revealed abolished PD‐1 and PD‐L1 interactions, improved T‐cell activity, and enhanced antitumor immunity in colon, breast, pancreatic, and kidney cancer models [338, 339, 340, 341].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [338] Yin H, Zhou X, Huang Y‐H, King GJ, Collins BM, Gao Y, et al. Rational Design of Potent Peptide Inhibitors of the PD‐1:PD‐L1 Interaction for Cancer Immunotherapy. J Am Chem Soc. 2021; 143(44): 18536– 47. 34661406 source

      Not checked in the free run.

    • cites [339] Gurung S, Khan F, Gunassekaran GR, Yoo JD, Poongkavithai Vadevoo SM, Permpoon U, et al. Phage display‐identified PD‐L1‐binding peptides reinvigorate T‐cell activity and inhibit tumor progression. Biomaterials. 2020; 247: 119984. 32278214 source

      Not checked in the free run.

    • cites [340] Vadevoo SMP, Gurung S, Khan F, Haque ME, Gunassekaran GR, Chi L, et al. Peptide‐based targeted therapeutics and apoptosis imaging probes for cancer therapy. Arch Pharmacal Res. 2019; 42(2): 150– 8. 30756310 source

      Not checked in the free run.

    • cites [341] Haque ME, Khan F, Chi L, Gurung S, Vadevoo SMP, Park R‐W, et al. A Phage Display‐Identified Peptide Selectively Binds to Kidney Injury Molecule‐1 (KIM‐1) and Detects KIM‐1‐Overexpressing Tumors in vivo. Cancer Treat Res Commun. 2019; 51(3): 861– 75. PMC6639206 30282451 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisecitation

    CAR-T cell therapy is ineffective in treating solid tumors and hematological malignancies.

    “However, many challenges remain to be addressed to overcome its ineffectiveness in treating solid tumors and hematological malignancies [350].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [350] Jogalekar MP, Rajendran RL, Khan F, Dmello C, Gangadaran P, Ahn B‐C. CAR T‐Cell‐Based gene therapy for cancers: new perspectives, challenges, and clinical developments. Front Immunol. 2022; 13: 925985. 35936003 PMC9355792 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Early administration of CAR-T cell therapy is associated with higher success rates and reduced toxicity.

    “The great potential of CAR‐T cell therapy at the beginning or earlier during the treatment course was unraveled, and the strategy revealed higher success rates and reduced toxicity associated with anticancer treatments [351].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [351] Krishnan A, Bhatia S, Slovak ML, Arber DA, Niland JC, Nademanee A, et al. Predictors of therapy‐related leukemia and myelodysplasia following autologous transplantation for lymphoma: an assessment of risk factors. Blood. 2000; 95(5): 1588– 93. 10688812 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationcitation

    The overall survival response for immune checkpoint immunotherapies is not enough and needs more comprehensive study.

    “Nonetheless, the overall survival response for these immunotherapies is not enough and needs a more comprehensive study [335].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [335] Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science (New York, NY). 2018; 359(6382): 1350– 5. PMC7391259 29567705 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tumor cells and tumor stroma express CCL2, and CCR2 is exclusively expressed by myeloid cells.

    “The tumor cells and tumor stroma are known to express CCL2, and the receptor CCR2 is exclusively expressed by myeloid cells [360, 361].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [360] Qian B‐Z, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, et al. CCL2 recruits inflammatory monocytes to facilitate breast‐tumour metastasis. Nature. 2011; 475(7355): 222– 5. 21654748 PMC3208506 source

      Not checked in the free run.

    • cites [361] Huang B, Lei Z, Zhao J, Gong W, Liu J, Chen Z, et al. CCL2/CCR2 pathway mediates recruitment of myeloid suppressor cells to cancers. Cancer Lett. 2007; 252(1): 86– 92. 17257744 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sabatolimab plus spartalizumab doses were under tolerance and showed anti-cancer activity with survival benefits in advanced solid tumors.

    “Several ongoing clinical trials investigating the blockade of TIM‐3 inhibitor (sabatolimab) with or without PD‐1 inhibitors in advanced solid tumors concluded that the doses for combination therapy of sabatolimab and spartalizumab were under tolerance and showed anti‐cancer activity with survival benefits [349].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [349] Curigliano G, Gelderblom H, Mach N, Doi T, Tai D, Forde PM, et al. Phase I/Ib Clinical Trial of Sabatolimab, an Anti‐TIM‐3 Antibody, Alone and in Combination with Spartalizumab, an Anti‐PD‐1 Antibody, in Advanced Solid Tumors. Clin Cancer Res. 2021; 27(13): 3620– 9. 33883177 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TAMs are bone marrow-derived myeloid cells that are part of tumor-associated stroma and are usually reprogrammed to perform immune suppressive and pro-tumor functions.

    “TAMs are bone marrow‐derived myeloid cells that are part of the tumor‐associated stroma and are usually reprogrammed to perform immune suppressive and pro‐tumor functions [358].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [358] Jakubzick CV, Randolph GJ, Henson PM. Monocyte differentiation and antigen‐presenting functions. Nat Rev Immunol. 2017; 17(6): 349– 62. 28436425 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Regulatory T cells suppress immune responses against tumors and maintain immune tolerance in physiological conditions.

    “Regulatory T cells suppress immune responses against tumors and their normal function to maintain immune tolerance in physiological conditions [352].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [352] Khor B. Regulatory T Cells: Central Concepts from Ontogeny to Therapy. Transfus Med Rev. 2017; 31(1): 36– 44. 27523957 PMC5161625 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Spheroids are the most widely used 3D tumor models that precisely model in vitro TME conditions including cellular heterogeneity, cell-cell interactions, cell-ECM interactions, signaling pathways, and gene expression profiles.

    “Spheroids are the most widely used 3D tumor models that precisely model in vitro conditions of a TME, including cellular heterogeneity, cell‐cell interactions, cell‐ECM interactions, signaling pathways, and gene expression profiles [376, 377].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [376] Costa EC, Moreira AF, de Melo‐Diogo D, Gaspar VM, Carvalho MP, Correia IJ. 3D tumor spheroids: an overview on the tools and techniques used for their analysis. Biotechnol Adv. 2016; 34(8): 1427– 41. 27845258 source

      Not checked in the free run.

    • cites [377] Rodrigues J, Heinrich MA, Teixeira LM, Prakash J. 3D In Vitro Model (R)evolution: Unveiling Tumor‐Stroma Interactions. Trends Cancer. 2021; 7(3): 249– 64. 33218948 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DCs are APCs that help in priming effector T cells and play an important role in regulating migration of CD8+ T cells into the TME.

    “DCs are APCs that help in priming effector T cells. DCs play an important role in regulating the migration of CD8+ T cells into the TME [363].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [363] Tan MC, Goedegebuure PS, Belt BA, Flaherty B, Sankpal N, Gillanders WE, et al. Disruption of CCR5‐dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. J Immunol. 2009; 182(3): 1746– 55. 19155524 PMC3738070 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In preclinical breast cancer models, anti-CCL2 blocking antibodies inhibited infiltrating monocytes and subsequent recruitment of metastasis-associated macrophages, inhibiting metastasis and prolonging lifespan of tumor-bearing mice.

    “In preclinical models of breast cancer, anti‐CCL2 blocking antibodies inhibited infiltrating monocytes and subsequent recruitment of metastasis‐associated macrophages, thereby inhibiting metastasis and prolonging the lifespan of tumor‐bearing mice [360].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [360] Qian B‐Z, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, et al. CCL2 recruits inflammatory monocytes to facilitate breast‐tumour metastasis. Nature. 2011; 475(7355): 222– 5. 21654748 PMC3208506 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Disrupting the CCL5-CCR5 axis may inhibit migration of TAMs, MDSCs, and Tregs and reduce tumor growth.

    “Moreover, disrupting the CCL5‐CCR5 axis may inhibit their migration and reduce tumor growth [362, 363].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [362] Soria G, Yaal‐Hahoshen N, Azenshtein E, Shina S, Leider‐Trejo L, Ryvo L, et al. Concomitant expression of the chemokines RANTES and MCP‐1 in human breast cancer: a basis for tumor‐promoting interactions. Cytokine. 2008; 44(1): 191– 200. 18790652 source

      Not checked in the free run.

    • cites [363] Tan MC, Goedegebuure PS, Belt BA, Flaherty B, Sankpal N, Gillanders WE, et al. Disruption of CCR5‐dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. J Immunol. 2009; 182(3): 1746– 55. 19155524 PMC3738070 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CCL3, CCL4, and CCL5 are ligands for CCR5 and are produced by various cell types including epithelial cells, fibroblasts, monocytes, NK cells, DCs, endothelial cells, macrophages, and lymphocytes.

    “CCL3, CCL44 and CCL55 are the ligands for CCR5 and are produced by various cell types like epithelial cells, fibroblasts, monocytes, NK cells, DCs, endothelial cells, macrophages and lymphocytes [364].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [364] Zhang Y, Guan X‐Y, Jiang P. Cytokine and Chemokine Signals of T‐Cell Exclusion in Tumors. Front Immunol. 2020; 11: 594609. 33381115 PMC7768018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CCL5 is produced by epithelial cells, fibroblasts, monocytes, NK cells, DCs, endothelial cells, macrophages, and lymphocytes; it acts as a ligand for CCR5 preferentially expressed by Tregs; and the CCL5-CCR5 axis induces migration of TAMs, MDSCs, and Tregs.

    “Similarly, CCL5, which is produced by epithelial cells, fibroblasts, monocytes, NK cells, DCs, endothelial cells, macrophages and lymphocytes, acts as a ligand for CCR5, preferentially expressed by Tregs, and the CCL5‐CCR5 signaling axis can induce the migration of TAMs, myeloid‐derived suppressive cells and that of regulatory T cells.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [362] Soria G, Yaal‐Hahoshen N, Azenshtein E, Shina S, Leider‐Trejo L, Ryvo L, et al. Concomitant expression of the chemokines RANTES and MCP‐1 in human breast cancer: a basis for tumor‐promoting interactions. Cytokine. 2008; 44(1): 191– 200. 18790652 source

      Not checked in the free run.

    • cites [363] Tan MC, Goedegebuure PS, Belt BA, Flaherty B, Sankpal N, Gillanders WE, et al. Disruption of CCR5‐dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. J Immunol. 2009; 182(3): 1746– 55. 19155524 PMC3738070 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a preclinical murine melanoma model, CCL20-positive tumor cells showed increased migration of DCs, indicating CCL20 attracts DCs to the tumor site.

    “A preclinical murine melanoma model showed increased migration of DCs in CCL20‐positive tumor cells, indicating the role of CCL20 in attracting DCs to the tumor site [368].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [368] Furumoto K, Soares L, Engleman EG, Merad M. Induction of potent antitumor immunity by in situ targeting of intratumoral DCs. J Clin Invest. 2004; 113(5): 774– 83. 14991076 PMC351319 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    p53 mutations in tumor cells are carcinogenic only in the presence of microbially produced gallic acid in the gut; otherwise, mutant p53 is more protective than wild-type p53 in tumor regression in mouse models of WNT-driven intestinal cancer.

    “For example, p53 mutations in tumor cells are carcinogenic only in the presence of microbially produced gallic acid in the gut; otherwise, mutant p53 was found to be more protective than wild‐type p53 in tumor regression in mouse models of WNT‐driven intestinal cancer [408].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [408] Kadosh E, Snir‐Alkalay I, Venkatachalam A, May S, Lasry A, Elyada E, et al. The gut microbiome switches mutant p53 from tumour‐suppressive to oncogenic. Nature. 2020; 586(7827): 133– 8. 32728212 PMC7116712 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The organoid model system has limitations including high variability, difficulty achieving in vitro-like maturity, lack of vasculature, immune-competent TME, and stroma.

    “However, the organoid model system has some limitations, including high variability and difficulty in achieving in vitro‐like maturity, lack of vasculature, an immune‐competent TME, and stroma [395].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [395] Dutta D, Heo I, Clevers H. Disease Modeling in Stem Cell‐Derived 3D Organoid Systems. Trends Mol Med. 2017; 23(5): 393– 410. 28341301 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microfluidic models allow fine control over mechanical forces, tissue interface orientation, and chemical gradients, and can be modified for high-throughput screening.

    “These models allow fine control over the mechanical forces, the orientation of the tissue interfaces, and chemical gradients, and they can be modified for high throughput screening [399, 400].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [399] Langhans SA. Three‐Dimensional in Vitro Cell Culture Models in Drug Discovery and Drug Repositioning. Front Pharmacol. 2018; 9: 6. 29410625 PMC5787088 source

      Not checked in the free run.

    • cites [400] Sung KE, Beebe DJ. Microfluidic 3D models of cancer. Adv Drug Deliv Rev. 2014; 79‐80: 68– 78. PMC4258433 25017040 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The reconstituted TME model recapitulates genetic and phenotypic features of a tumor and models the functional response of a patient to therapeutic agents.

    “The reconstituted TME model recapitulates not only the genetic and phenotypic features of a tumor but also models the functional response of a patient to therapeutic agents [389, 390].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [389] van de Wetering M, Francies HE, Francis JM, Bounova G, Iorio F, Pronk A, et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell. 2015; 161(4): 933– 45. 25957691 PMC6428276 source

      Not checked in the free run.

    • cites [390] Yan HHN, Siu HC, Law S, Ho SL, Yue SSK, Tsui WY, et al. A Comprehensive Human Gastric Cancer Organoid Biobank Captures Tumor Subtype Heterogeneity and Enables Therapeutic Screening. Cell Stem Cell. 2018; 23(6): 882– 97.e11. 30344100 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Kras mutation and loss of p53 failed to promote lung tumorigenesis in antibiotic-treated/germ-free mice because lung microbiota can promote tumorigenesis via IL-23 and IL-17 production, leading to tumor-promoting inflammation.

    “Moreover, Kras mutation and loss of p53 failed to promote lung tumorigenesis in antibiotic‐treated/germ‐free mice because lung microbiota could promote tumorigenesis via IL‐23 and IL‐17 production, leading to tumor‐promoting inflammation [409].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [409] Jin C, Lagoudas GK, Zhao C, Bullman S, Bhutkar A, Hu B, et al. Commensal Microbiota Promote Lung Cancer Development via γδ T Cells. Cell. 2019; 176(5): 998– 1013.e16. 30712876 PMC6691977 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Organoids are small 3D self-organized tissue cultures derived from progenitor stem cells that maintain natural cancer cell heterogeneity in vitro, including genetic and phenotypic features of the tissue of origin.

    “Organoids are small 3D self‐organized tissue cultures derived from progenitor stem cells that maintain natural cancer cell heterogeneity in vitro, including genetic and phenotypic features of the tissue from which the culture is derived [383, 384].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [383] Drost J, Clevers H. Organoids in cancer research. Nat Rev Cancer. 2018; 18(7): 407– 18. 29692415 source

      Not checked in the free run.

    • cites [384] Fan H, Demirci U, Chen P. Emerging organoid models: leaping forward in cancer research. J Hematol Oncol. 2019; 12(1): 142. 31884964 PMC6936115 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Only 11 microbial species are known to directly cause carcinogenesis, while other microbes promote tumorigenesis but are insufficient to cause it alone.

    “Although only 11 microbial species are known to directly cause carcinogenesis [407], a category of microbes and their functions promote tumorigenesis but are insufficient to cause tumorigenesis on their own.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [407] IWGotEoCRt H. Biological agents. IARC monographs on the evaluation of carcinogenic risks to humans. 2012; 100(Pt B): 1– 441. PMC4781184 23189750

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Organoids are more advantageous than PDX and other tumor-bearing animal models due to ease of culturing and closer resemblance to the TME, making them more pathophysiologically relevant.

    “Moreover, organoids are more advantageous due to the ease of culturing and closer resemblance to the TME, thus being more pathophysiologically relevant as compared to the patient‐derived tumor xenograft (PDX) model and other tumor‐bearing animal models, which are more tedious and expensive to maintain [384, 395].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [384] Fan H, Demirci U, Chen P. Emerging organoid models: leaping forward in cancer research. J Hematol Oncol. 2019; 12(1): 142. 31884964 PMC6936115 source

      Not checked in the free run.

    • cites [395] Dutta D, Heo I, Clevers H. Disease Modeling in Stem Cell‐Derived 3D Organoid Systems. Trends Mol Med. 2017; 23(5): 393– 410. 28341301 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Spheroid 3D models have limitations including poor uniformity in size/morphology, low throughput, and difficulty retrieving cells for analyses, which limit reproducibility.

    “Nonetheless, there are certain limitations, including 1) poor uniformity in spheroid size or morphology, 2) low throughput, and 3) difficulties in retrieving cells for analyses, etc., in the 3D spheroid models that limit reproducibility while using these models [377].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [377] Rodrigues J, Heinrich MA, Teixeira LM, Prakash J. 3D In Vitro Model (R)evolution: Unveiling Tumor‐Stroma Interactions. Trends Cancer. 2021; 7(3): 249– 64. 33218948 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Probiotics increase anticancer immunity by decreasing Treg levels and enhancing CD4+ T cell differentiation, CD8+ T cell activation, and intratumoral infiltration of NK cells.

    “Probiotics increase anticancer immunity by decreasing Treg levels and enhancing CD4+ T cell differentiation, CD8+ T cell activation, and intratumoral infiltration of NK cells [427, 428].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [427] Jacouton E, Chain F, Sokol H, Langella P, Bermúdez‐Humarán LG. Probiotic Strain Lactobacillus casei BL23 Prevents Colitis‐Associated Colorectal Cancer. Front Immunol. 2017; 8: 1553. 29209314 PMC5702231 source

      Not checked in the free run.

    • cites [428] Hu J, Wang C, Ye L, Yang W, Huang H, Meng F, et al. Anti‐tumour immune effect of oral administration of Lactobacillus plantarum to CT26 tumour‐bearing mice. J Biosci. 2015; 40(2): 269– 79. 25963256 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microbes promote cytotoxin-associated gene A- or T cell-mediated inflammation in stomach and lung cancers, respectively.

    “promote cytotoxin‐associated gene A‐ or T cell‐mediated inflammation as shown in stomach and lung cancers, respectively [409, 414]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [409] Jin C, Lagoudas GK, Zhao C, Bullman S, Bhutkar A, Hu B, et al. Commensal Microbiota Promote Lung Cancer Development via γδ T Cells. Cell. 2019; 176(5): 998– 1013.e16. 30712876 PMC6691977 source

      Not checked in the free run.

    • cites [414] Suzuki M, Mimuro H, Kiga K, Fukumatsu M, Ishijima N, Morikawa H, et al. Helicobacter pylori CagA phosphorylation‐independent function in epithelial proliferation and inflammation. Cell Host & Microbe. 2009; 5(1): 23– 34. 19154985 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cyclophosphamide alters intestinal microbiota in mice and promotes pathogenic Th17 cell production; removing gut microbiota via antibiotics leads to drug resistance.

    “The chemotherapeutic agent, cyclophosphamide, was shown to alter intestinal microbiota in mice and promote “pathogenic” Th17 cell production [422]; however, removing gut microbiota via antibiotic treatment led to drug resistance [423, 424].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [422] Cheng WY, Wu C‐Y, Yu J. The role of gut microbiota in cancer treatment: friend or foe? Gut. 2020; 69(10): 1867– 76. 32759302 PMC7497589 source

      Not checked in the free run.

    • cites [423] Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillère R, Hannani D, et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science (New York, NY). 2013; 342(6161): 971– 6. PMC4048947 24264990 source

      Not checked in the free run.

    • cites [424] Viaud S, Flament C, Zoubir M, Pautier P, LeCesne A, Ribrag V, et al. Cyclophosphamide induces differentiation of Th17 cells in cancer patients. Cancer Res. 2011; 71(3): 661– 5. 21148486 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Probiotics such as L. acidophilus NCFM increase butyrate-producing species in the gut, leading to improved immunotherapy response.

    “Moreover, probiotics, such as L. acidophilus NCFM, increase butyrate‐producing species in the gut, leading to improved immunotherapy response [429, 430].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [429] Frankel AE, Coughlin LA, Kim J, Froehlich TW, Xie Y, Frenkel EP, et al. Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint Therapy Efficacy in Melanoma Patients. Neoplasia (New York, NY). 2017; 19(10): 848– 55. PMC5602478 28923537 source

      Not checked in the free run.

    • cites [430] Chaput N, Lepage P, Coutzac C, Soularue E, Le Roux K, Monot C, et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol: Official Journal of the European Society for Medical Oncology. 2017; 28(6): 1368– 79. 28368458 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microbes advance metastasis by upregulating tumor MMPs or reducing infiltrating immune cells.

    “and even advance metastasis by upregulating tumor MMPs or by reducing infiltrating immune cells [418, 419].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [418] Parhi L, Alon‐Maimon T, Sol A, Nejman D, Shhadeh A, Fainsod‐Levi T, et al. Breast cancer colonization by Fusobacterium nucleatum accelerates tumor growth and metastatic progression. Nat Commun. 2020; 11(1): 3259. 32591509 PMC7320135 source

      Not checked in the free run.

    • cites [419] Le Noci V, Guglielmetti S, Arioli S, Camisaschi C, Bianchi F, Sommariva M, et al. Modulation of Pulmonary Microbiota by Antibiotic or Probiotic Aerosol Therapy: A Strategy to Promote Immunosurveillance against Lung Metastases. Cell Rep. 2018; 24(13): 3528– 38. 30257213 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Transformed cancer cells invade normal, healthy cells in their vicinities, such as immune cells and fibroblasts, to counter stress, nutrient deprivation, and hypoxia.

    “Transformed cancer cells invade normal, healthy cells in their vicinities, such as immune cells and fibroblasts, to counter stress, nutrient deprivation, and hypoxia.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Diet, chemotherapy, antibiotics, probiotics, and hormones all play a role in modulating the TME microbiota.

    “Thus, diet, chemotherapy, antibiotics, probiotics, and hormones all play a role in modulating the TME microbiota [437, 438].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [437] Shida K, Nomoto K. Probiotics as efficient immunopotentiators: translational role in cancer prevention. Indian J Med Res. 2013; 138(5): 808– 14. 24434333 PMC3928711

      Not checked in the free run.

    • cites [438] Eslami‐S Z, Majidzadeh‐A K, Halvaei S, Babapirali F, Esmaeili R. Microbiome and Breast Cancer: New Role for an Ancient Population. Front Oncol. 2020; 10: 120. 32117767 PMC7028701 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). The quote only partly states this claim.

    Interpretationnone given

    Therapeutic strategies that disrupt the crosstalk between tumor cells and the TME lead to better patient outcomes.

    “Preclinical research efforts are focused on developing therapeutic strategies that disrupt the crosstalk between tumor cells and the TME, leading to better patient outcomes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Gut microbiota plays a crucial role in tumorigenesis via their immunomodulatory abilities.

    “Furthermore, gut microbiota plays a crucial role in tumorigenesis via their immunomodulatory abilities.”
    Quote in the paperNot a substantial claim
121 of 121

  • The paper relies on this without support.

    The chemokine gradient determines the composition of the TME.

    “The chemokine gradient determines the composition of the TME.”

  • The paper relies on this without support.

    A pro-tumor chemokine gradient attracts immune suppressive immune cells and excludes effector immune cells.

    “Pro‐tumor chemokine gradient attracts immune suppressive immune cells and excludes effector immune cells.”

  • The paper relies on this without support.

    An antitumor chemokine gradient favors the migration of effector immune cells.

    “On the other hand, the antitumor chemokine gradient favors the migration of effector immune cells.”

  • The paper relies on this without support.

    CCL3, CCL4, and CCL5 form a cytokine gradient that can recruit DCs into the TME.

    “CCL3, CCL4 and CCL5 form a cytokine gradient that can recruit DCs into the TME.”

  • The paper relies on this without support.

    Cytokine signaling is important for tumor development and the recognition of tumors by immune cells.

    “Cytokine signaling is important for tumor development and the recognition of tumors by immune cells.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The tumor microenvironment significantly influences drug penetration, retention, and therapeutic response.

    “Together, these components create a tumor microenvironment (TME) that significantly influences drug penetration, retention, and therapeutic response [1,3,4].”

    From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [4]

    In “TME-based cancer therapy” (page unavailable), the review says poor tumor vasculature protects the tumor core from therapeutics delivered through the bloodstream, supporting an effect on drug penetration. The same section describes microenvironmental factors altering treatment response and ECM-targeted agents localizing treatment in tumors, but it does not establish an effect on drug retention specifically. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Siglec groups have overlapping members

    Minor

    The text says siglecs are divided into two groups, but assigns siglecs 5-11 and 14-15 to both groups.

  • CCR5 ligand lists disagree

    Minor

    Consecutive sentences identify the CCR5 ligands as CCL3, CCL44 and CCL55, then identify the relevant gradient as CCL3, CCL4 and CCL5.

  • Checkpoint-blockade description reverses its stated effect on T cells

    Minor

    The immunotherapy section says its treatments attenuate T-cell function, whereas the accompanying figure says checkpoint blockade restores it.

  • Nivolumab-ipilimumab regimen omits its stated CTLA4 target

    Minor

    Table 2 identifies PD-L1 alone as the target of the nivolumab-ipilimumab mesothelioma regimen, but the text identifies ipilimumab as anti-CTLA4.

4 of 4

The citation lists haven’t been fetched yet

References 439 · Cited by 323

Authors
Goenka, A., Khan, F., Verma, B., Sinha, P., Dmello, C. C., Jogalekar, M. P., Gangadaran, P., & Ahn, B.
Affiliations
  • Northwestern University (US)
  • Massachusetts Eye and Ear Infirmary (US)
  • Harvard University (US)
  • University of California, San Francisco (US)
  • Kyungpook National University Hospital (KR)
Corresponding author
  • Goenka, Anshika
  • Gangadaran, Prakash
  • Ahn, Byeong‐Cheol
ORCID
Venue
Cancer Communications
Publisher
American Association for the Advancement of Science (AAAS)
Published
2023-04-02
Volume
43
Issue
5
Pages
525-561
ISSN
  • 1000-467X (ISSN-L)
  • 2523-3548
DOI
10.1002/cac2.12416
PMC
PMC10174093
OpenAlex
W4362505682
Semantic Scholar
9f22edba1520bda360bd0a92cc0d0e7b0e0e4833
Cited by
323
References
439
Citations by year
2026: 113 · 2025: 121 · 2024: 77 · 2023: 12
FWCI
10.42
Type
journal article
Language
en
Open access
Licence
Locations
  • 癌症：英文版 (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Research Foundation of Korea (NRF) grant funded by the Korea government (NRF‐2022R1A2C2005057)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
tumor microenvironment, tumor progression, tumor stroma, extracellular matrix, tumor invasion, immune checkpoint, PD-1, CTLA-4, TIM-3, LAG-3, chemokine signaling, CCR4, CCR2, MCP-1, CCR5, CCL3, protein kinase C signaling, Notch signaling, TGF-beta signaling, endoplasmic reticulum stress, lactate signaling, metabolic reprogramming, cGAS-STING pathway, microfluidic model, gut microbiota, cancer immunotherapy
MeSH terms
Humans, Neoplasms, Neoplastic Processes, Signal Transduction, Chemokines, Receptors, Chemokine, Tumor Microenvironment

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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