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Cited by 119Cancer, Hypoxia, and MetabolismAngiogenesis and VEGF in CancerCancer Cells and Metastasis

Hypoxia signaling in cancer: Implications for therapeutic interventions

Open access
Zhuang, Yan, Liu, Kua, He, Qinyu, Gu, Xiaosong, Jiang, Chunping, Wu, Junhua·2023·MedComm
DOI 10.1002/mco2.203PMC PMC9870816
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Abstract

Hypoxia is a persistent physiological feature of many different solid tumors and a key driver of malignancy, and in recent years, it has been recognized as an important target for cancer therapy. Hypoxia occurs in the majority of solid tumors due to a poor vascular oxygen supply that is not sufficient to meet the needs of rapidly proliferating cancer cells. A hypoxic tumor microenvironment (TME) can reduce the effectiveness of other tumor therapies, such as radiotherapy, chemotherapy, and immunotherapy. In this review, we discuss the critical role of hypoxia in tumor development, including tumor metabolism, tumor immunity, and tumor angiogenesis. The treatment methods for hypoxic TME are summarized, including hypoxia‐targeted therapy and improving oxygenation by alleviating tumor hypoxia itself. Hyperoxia therapy can be used to improve tissue oxygen partial pressure and relieve tumor hypoxia. We focus on the underlying mechanisms of hyperoxia and their impact on current cancer therapies and discuss the prospects of hyperoxia therapy in cancer treatment.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes how tumor hypoxia and HIF signaling drive metabolic reprogramming, angiogenesis, metastasis, DNA repair, and immune escape, and discusses therapies targeting hypoxia or improving oxygenation. It argues hyperoxia is promising mainly as an adjuvant to radiotherapy, chemotherapy, immunotherapy, and photodynamic therapy, though clinical implementation and mechanisms remain unresolved.

Key findings

  • Hypoxia is common in solid tumors; at 70–150 μm from tumor blood vessels, oxygen tension falls below 10 mmHg, and HIF-1α is described as the master transcriptional regulator. HIF-1 DNA-binding activity and HIF-1α/HIF-1β protein levels increased exponentially as O2 decreased from 20% to 0.125%.
  • Hypoxia promotes malignancy through metabolic reprogramming (Warburg effect, glucose/glutamine pathways), angiogenesis (VEGF), EMT/metastasis, DNA damage repair (ATR/Chk1, ATM/Chk2), and immune escape (PD-L1, MDSCs, TAMs, altered T-cell function).
  • Therapeutic strategies include HIF inhibitors (e.g., PT2385, belzutifan, PT2399), gene therapy, hypoxia-activated prodrugs such as tirapazamine, nanoparticles, mTOR/acidic TME targeting, and oxygenation methods including normobaric/hyperbaric oxygen, carbogen, oxygen carriers, hyperthermia, vascular normalization, and inhibition of tumor cell respiration.
  • Hyperoxia can sensitize tumors: radiation under well-oxygenated conditions increases biological effects approximately 3-fold versus hypoxia; hyperoxia raises tissue pO2 more than 10 times normoxia. In PDT/HBO clinical pilots, median overall survival was 12 vs 7 months and 12-month survival was 41.2% vs 28.6%, though some HBO trials for radiation late effects showed no benefit.

Methods

  • Narrative review; the authors synthesize literature on hypoxia signaling and therapeutic interventions, including preclinical and clinical studies, with figures and summary tables.
  • No systematic search strategy, inclusion/exclusion criteria, or meta-analysis is described; evidence includes cell lines, mouse models, and clinical trials.
  • Main analysis is thematic: mechanisms of hypoxia in tumor progression; hypoxia-targeted therapies; methods to improve oxygenation; and hyperoxia as an adjunct in radiotherapy, chemotherapy, immunotherapy, and PDT.

Limitations

  • Stated: timing of hyperoxia intervention, optimal oxygen concentration/duration, oxygen poisoning, unknown optimal oxygen levels for each tissue/disease/individual, and incomplete mechanisms—especially immune recruitment—remain unresolved.
  • Stated: hyperoxia-assisted immunotherapy evidence is mainly from mouse models and has not been tested in humans; clinical application of hyperoxia combined with PDT still needs further research.
  • Evident from the text: as a narrative review, it lacks systematic search/quality appraisal and quantitative synthesis; cited studies are heterogeneous in tumor types, oxygen regimens, and endpoints, limiting direct comparisons.

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Integrity signals

Registry

Crossref · 10.1002/mco2.203

Cites

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Statistics

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Claims the paper makes

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  • Premisecitation

    Hypoxia occurs in the majority of solid tumors due to a poor vascular oxygen supply that is not sufficient to meet the needs of rapidly proliferating cancer cells.

    “Hypoxia occurs in the majority of solid tumors due to a poor vascular oxygen supply that is not sufficient to meet the needs of rapidly proliferating cancer cells.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Bennewith KL, Dedhar S. Targeting hypoxic tumour cells to overcome metastasis. BMC Cancer. 2011; 11: 504. 22128892 PMC3247198 source

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  • Premisecitation

    HIF-1α is considered a master transcriptional regulator of the tumor cell response to hypoxia.

    “HIF‐1α is considered to be a master transcriptional regulator of the tumor cell response to hypoxia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Blouw B, Song H, Tihan T, et al. The hypoxic response of tumors is dependent on their microenvironment. Cancer Cell. 2003; 4(2): 133‐ 146. 12957288 source

      Not checked in the free run.

  • Premisecitation

    Hypoxia-induced upregulation of HIF-1 leads to activation of VEGF.

    “Hypoxia‐induced upregulation of HIF‐1 also leads to the activation of vascular endothelial growth factor (VEGF).”
    Quote in the paperSubstantial claim0 of 1 sources checked
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      Not checked in the free run.

  • Premisenone given

    A hypoxic tumor microenvironment can reduce the effectiveness of other tumor therapies, such as radiotherapy, chemotherapy, and immunotherapy.

    “A hypoxic tumor microenvironment (TME) can reduce the effectiveness of other tumor therapies, such as radiotherapy, chemotherapy, and immunotherapy.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    VHL gene mutations lead to stability of HIF subunits and constitutive activation of HIF-mediated transcriptional pathways in patients with VHL, causing progression of renal cell carcinoma.

    “VHL gene mutations lead to the stability of HIF subunits and the constitutive activation of HIF‐mediated transcriptional pathways in patients with VHL, causing the progression of renal cell carcinoma.”
    Quote in the paperSubstantial claim0 of 3 sources checked
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      Not checked in the free run.

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  • Classified as probably not a substantial claim. 8

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    Premisecitation

    The VHL protein acts as an E3 ubiquitin ligase and ubiquitinates HIF-α in an oxygen-dependent manner, resulting in proteolysis of HIF.

    “The VHL protein acts as an E3 ubiquitin ligase and can ubiquitinate the HIF‐α subunit in an oxygen‐dependent manner, resulting in the proteolysis of HIF.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [24] Jonasch E, Donskov F, Iliopoulos O, et al. Belzutifan for renal cell carcinoma in von Hippel‐Lindau disease. N Engl J Med. 2021; 385(22): 2036‐ 2046. 34818478 PMC9275515

      Not checked in the free run.

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    • cites [26] Krishnan B, Rose TL, Kardos J, Milowsky MI, Kim WY. Intrinsic genomic differences between African American and White patients with clear cell renal cell carcinoma. JAMA Oncol. 2016; 2(5): 664‐ 667. 27010573 PMC5035632

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    Premisecitation

    Cancer cells cultured in hypoxic environments have significantly higher proliferation, invasion, and metastasis activities than cells in normal oxygen-containing environments.

    “Researchers have cultured cancer cells in normal and hypoxic environments and found that the proliferation, invasion, and metastasis activities of cells are significantly higher in hypoxic environments than in normal oxygen‐containing environments.”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Premisecitation

    Hyperoxia therapy can be used to improve tissue oxygen partial pressure and relieve tumor hypoxia.

    “Hyperoxia therapy can be used to improve tissue oxygen partial pressure and relieve tumor hypoxia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    At the periphery of a tumor, 70-150 μm away from the tumor blood vessels, the available oxygen is consumed by rapidly proliferating cells, limiting diffusion into deep layers and resulting in oxygen tension below 10 mmHg.

    “At the periphery of a tumor, 70–150 μm away from the tumor blood vessels, the available oxygen is consumed by rapidly proliferating cells, which limits the diffusion of oxygen into the deep layers of the tumor, resulting in oxygen tension below 10 mmHg, known as tumor hypoxia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Bennewith KL, Dedhar S. Targeting hypoxic tumour cells to overcome metastasis. BMC Cancer. 2011; 11: 504. 22128892 PMC3247198

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    Premisecitation

    The formation of a chronic hypoxic environment activates HIF signaling, accelerates tumor growth, improves tumor invasiveness, and promotes tumor metastasis.

    “of a chronic hypoxic environment activates the signaling pathway of hypoxia‐inducible factors (HIFs), accelerates tumor growth, improves tumor invasiveness, and promotes tumor metastasis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] LaGory EL, Giaccia AJ. The ever‐expanding role of HIF in tumour and stromal biology. Nat Cell Biol. 2016; 18(4): 356‐ 365. 27027486 PMC4898054

      Not checked in the free run.

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    Premisecitation

    Hypoxia is a persistent physiological feature of many different solid tumors and a key driver of malignancy.

    “Hypoxia is a persistent physiological feature of many different solid tumors and a key driver of malignancy, and in recent years, it has been recognized as an important target for cancer therapy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Bennewith KL, Dedhar S. Targeting hypoxic tumour cells to overcome metastasis. BMC Cancer. 2011; 11: 504. 22128892 PMC3247198

      Not checked in the free run.

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    Premisecitation

    HIF-1α can induce tumor-associated macrophages to secrete IL-23, which activates regulatory T cell proliferation, promotes IL-10 and TGF-β expression, and inhibits cytotoxic lymphocyte killing of tumor cells.

    “HIF‐1α can also induce TAMs to secrete IL‐23, which activates the proliferation of regulatory T cells (Tregs), promotes the expression of IL‐10 and TGF‐β, and thus inhibits the capacity of cytotoxic lymphocytes to kill tumor cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisenone given

    HAPs have cytotoxic effects only in hypoxic environments and show reduced side effects in normal tissues under normoxic conditions.

    “HAPs are important drugs for the treatment of hypoxic tumors because they have cytotoxic effects only in hypoxic environments and show reduced side effects in normal tissues under normoxic conditions.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Hypoxia maintains the function of myeloid-derived suppressor cells, which have immunosuppressive activity, allowing cancer cells to escape immune surveillance and resist immune checkpoint blockade.

    “Hypoxia maintains the function of myeloid‐derived suppressor cells (MDSCs), which have immunosuppressive activity, allowing cancer cells to escape immune surveillance and resist immune checkpoint blockade.”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Premisecitation

    HIF-1α downregulates dicer expression by promoting ubiquitination of the E3 ligase parkin, which further inhibits known tumor suppressors such as let-7 and microRNA-200B.

    “HIF‐1α downregulates the expression of dicer by promoting ubiquitination of the E3 ligase parkin, which further inhibits known tumor suppressors, such as the microRNAs let‐7 and microRNA‐200B.”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Premisecitation

    Targeting HIF-1α reverses immune dysfunction and overcomes resistance to PD-L1 blockade.

    “Targeting HIF‐1α reverses immune dysfunction and overcomes resistance to PD‐L1 blockade.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    Some findings indicate that O2 is required for T-cell activation and development of effector functions and that HIF-1α acts as a negative regulator of T-cell responses.

    “Some findings have indicated that O2 is required for T‐cell activation and the development of effector functions and that HIF‐1α acts as a negative regulator of T‐cell responses.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    2-hydroxyglutarate is produced by CD8+ T lymphocytes in response to T-cell receptor triggering and environmental hypoxia, and it significantly boosts proliferation, persistence, and antitumor capacity of CD8+ T lymphocytes in vivo.

    “2‐hydroxyglutarate (2‐HG) is produced by CD8+ T lymphocytes in response to T‐cell receptor triggering and environmental hypoxia, and 2‐HG significantly boosts the proliferation, persistence, and antitumor capacity of CD8+ T lymphocytes in vivo.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    HIF-1-induced proteins include VEGF, which promotes vascular permeability, and bFGF, which promotes endothelial cell growth.

    “HIF‐1‐induced proteins include VEGF, which promotes vascular permeability, and basic fibroblast growth factor (bFGF), which promotes endothelial cell growth.”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Premisecitation

    In the hypoxic environment of the internal tumor mass, the HIF-1 dimeric complex remains stable and activates expression of numerous genes responsible for angiogenesis.

    “In the hypoxic environment of the internal tumor mass, the HIF‐1 dimeric complex remains stable and activates the expression of numerous genes responsible for the angiogenesis process.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    HIF-2α-induced expression of SLC1A5 mediates glutamine-induced ATP production and glutathione synthesis and renders pancreatic cancer resistant to gemcitabine.

    “HIF‐2α‐induced expression of the glutamine transporter solute carrier family 1, member 5 (SLC1A5) mediates glutamine‐induced ATP production and glutathione synthesis and renders pancreatic cancer resistant to gemcitabine.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    The stability of HIF-1α is regulated by α-KG, and increasing α-KG reduces HIF-1α expression.

    “The stability of HIF‐1α is regulated by α‐KG, and increasing α‐KG reduces the expression of HIF‐1α.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    Loss of SHMT2 in hypoxic cells increases reactive oxygen species levels, resulting in cell death.

    “Loss of SHMT2 in hypoxic cells increases reactive oxygen species (ROS) levels, resulting in cell death.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    Traditional angiogenesis inhibitors mainly block VEGF signaling and prune rather than eradicate tumor vessels.

    “Traditional angiogenesis inhibitors mainly block VEGF signaling and prune rather than eradicate tumor vessels.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    VEGF is highly expressed in most human cancer cell types, and hypoxia is a major inducer of VEGF gene transcription.

    “VEGF is highly expressed in most human cancer cell types, and hypoxia has been shown to be a major inducer of VEGF gene transcription (Figure 1).”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Premisecitation

    Respiratory hyperoxia improves tumor oxygenation, which can have multiple beneficial effects as a cancer treatment modality.

    “Multiple studies have been conducted showing that respiratory hyperoxia improves tumor oxygenation, which can have multiple beneficial effects as a cancer treatment modality.”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Premisecitation

    HBO can inhibit hypoxia-activated STAT3, slowing tumor growth and drug resistance.

    “HBO can inhibit the hypoxia‐activated signal transducer and activator of transcription 3 (STAT3), slowing tumor growth and drug resistance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    Inhalation of different CO2 concentrations showed different effects on the time course of tumor oxygenation changes; with high CO2 concentrations, perfusion remained elevated for at least 30 min, and higher inhaled CO2 (2.5% or 5%) prolonged the time to improvement in tumor perfusion compared with pure oxygen.

    “Inhalation of different CO2 concentrations showed different effects on the time course of tumor oxygenation changes. The perfusion recovered to its starting value immediately after the end of hyperoxia (pure oxygen), whereas with high concentrations of CO2, the perfusion remained elevated for at least 30 min. Higher inhaled CO2 concentrations (2.5% or 5%) prolonged the time to improvement in tumor”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisereasoning

    Because HBOCs can regulate oxygen delivery in the circulatory system, hemoglobin therapy is a promising oxygen therapy that can enhance the efficacy of other tumor therapies such as radiotherapy and chemotherapy.

    “Because HBOCs can regulate oxygen delivery in the circulatory system, hemoglobin therapy is a promising oxygen therapy that can enhance the efficacy of other tumor therapies, such as radiotherapy and chemotherapy.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
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  • May combine two claims.

    Interpretationreasoning

    Compared with atmospheric hyperoxia and hyperbaric hyperoxia, delivery of nanomaterials can more specifically target tumor tissues and improve tumor oxygenation.

    “Compared with atmospheric hyperoxia and hyperbaric hyperoxia, which improve tumor pO2, the delivery of nanomaterials can more specifically target tumor tissues and improve tumor oxygenation.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Carbogen respiration appears to have a greater effect on tumor oxygenation than respiration hyperoxia because carbogen induces vasodilation and increases blood flow to facilitate oxygen delivery.

    “Carbogen respiration appears to have a greater effect on tumor oxygenation than respiration hyperoxia because carbogen induces vasodilation and increases blood flow to facilitate oxygen delivery.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisereasoning

    Blood vessels in tumor tissues differ from normal tissues and have a higher density, with large gaps between endothelial cells and an EPR effect, so nanomaterials can target tumor tissue and improve drug accumulation.

    “Blood vessels in tumor tissues are very different from those in normal tissues and have a higher density. There is a large gap between vascular endothelial cells, and the blood vessels of tumor tissue have an EPR effect; therefore, nanomaterials can target tumor tissue and improve the accumulation of drugs in tumor tissue.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Fluorocarbon-DA (Fluosol-DA) is the only perfluorochemical O2 carrier approved for clinical use by the FDA, but it has been withdrawn from the market due to cumbersome implementation and limited efficacy.

    “The only perfluorochemical O2 carrier approved for clinical use by the Food and Drug Administration (FDA) is fluorocarbon‐DA (Fluosol‐DA), but it has been withdrawn from the market due to its cumbersome implementation and limited efficacy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Interpretationcitation

    The beneficial effect of mTOR inhibitor alone may be due to inhibition of HIF-1α.

    “The beneficial effect of the mTOR inhibitor alone may be due to the inhibition of HIF‐1α.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    Perfluorinated compounds are synthetic biologically inert compounds, and aqueous emulsions of fluorinated hydrocarbons can dissolve large amounts of oxygen.

    “Perfluorinated compounds are synthetic biologically inert compounds, and aqueous emulsions of fluorinated hydrocarbons are capable of dissolving large amounts of oxygen.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    In triple-negative breast cancer, HBO treatment can alleviate tumor hypoxia, thereby inhibiting tumor growth and metastasis.

    “In triple‐negative breast cancer, HBO treatment can alleviate tumor hypoxia, thereby inhibiting tumor growth and metastasis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    Hypoxic tumor cells show reduced intracellular pH compared with normal cells because tumors exhibit elevated metabolism, an acidic pH, and nutrient and oxygen deficiencies.

    “Hypoxic tumor cells show reduced intracellular pH compared with normal cells because tumors exhibit elevated metabolism, an acidic pH, and nutrient and oxygen deficiencies.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Harris AL. Hypoxia–a key regulatory factor in tumour growth. Nat Rev Cancer. 2002; 2(1): 38‐ 47. 11902584

      Not checked in the free run.

    • cites [186] Ovais M, Mukherjee S, Pramanik A, et al. Designing stimuli‐responsive upconversion nanoparticles that exploit the tumor microenvironment. Adv Mater. 2020; 32(22): e2000055. 32227413

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sun demonstrated that HT (41°C, 30/45 min) had different effects on tumor oxygenation in different regions in a xenograft model; overall tumor oxygenation improved during and after heating but the effect was transient.

    “Sun demonstrated that the effect of HT (41°C, 30/45 min) on tumor oxygenation was different in different regions in a xenograft model. Overall, tumor oxygenation improved during and after heating, but the effect was transient.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [248] Sun X, Li XF, Russell J, et al. Changes in tumor hypoxia induced by mild temperature hyperthermia as assessed by dual‐tracer immunohistochemistry. Radiother Oncol. 2008; 88(2): 269‐ 276. 18538874 PMC2612785

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hyperoxia (60% O2) can reverse the immunosuppressive TME and promote antitumor immunity.

    “Hyperoxia (60% O2) can also reverse the immunosuppressive TME and promote antitumor immunity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [206] Hatfield SM, Kjaergaard J, Lukashev D, et al. Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci Transl Med. 2015; 7(277): 277ra30. PMC4641038 25739764

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Based on clinical results, HBO improves tumor oxygenation, and use of HBO during radiotherapy improves the radiation response of solid tumors.

    “Based on clinical results, HBO has the effect of improving tumor oxygenation, and the use of HBO during radiotherapy has been proven to improve the radiation response of solid tumors.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [212] Overgaard J. Sensitization of hypoxic tumour cells–clinical experience. Int J Radiat Biol. 1989; 56(5): 801‐ 811. 2573679

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    No HBOCs have yet been clinically approved, mainly due to unaddressed side effects such as nephrotoxicity and elevated hypertension.

    “Although HBOCs have been studied for decades and have undergone several generations, no HBOCs have yet been clinically approved. This is mainly due to side effects associated with HBOCs that have not been addressed, such as nephrotoxicity and elevated hypertension.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [231] Palmer AF, Intaglietta M. Blood substitutes. Annu Rev Biomed Eng. 2014; 16: 77‐ 101. 24819476

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The neutral layer of LbL nanoparticles is shed in acidic environments, exposing charged nanoparticles that can be absorbed by tumor cells.

    “The neutral layer is shed in acidic environments, exposing a surface of charged nanoparticles, which can be easily absorbed by tumor cells.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [187] Poon Z, Chang D, Zhao X, Hammond PT. Layer‐by‐layer nanoparticles with a pH‐sheddable layer for in vivo targeting of tumor hypoxia. ACS Nano. 2011; 5(6): 4284‐ 4292. 21513353 PMC3125426

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Variations in tumor blood circulation can create physiological changes including enhanced vascular permeability, increased oxygenation, decreased interstitial fluid pressure, and restoration of normal physiological pH.

    “Variations in blood circulation in tumors can create dramatic physiological changes, including enhanced vascular permeability, increased oxygenation, decreased interstitial fluid pressure, and restoration of normal physiological pH.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [241] Dunne M, Regenold M, Allen C. Hyperthermia can alter tumor physiology and improve chemo‐ and radio‐therapy efficacy. Adv Drug Deliv Rev. 2020; 163‐164: 98‐ 124. 32681862

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Thrall et al. treated 37 cases of spontaneous canine tumors with 30 CEM43T90 fractions; compared with baseline, tumor PO2 was significantly increased in both treatment groups.

    “Thrall et al. treated 37 cases of spontaneous canine tumors with fractions of an equivalent total thermal dose of 30 CEM43T90 (a thermodosimetric measure, taking into account the 90th percentile temperature, not the median temperature of CEM43) divided weekly, and the animals received 1 or 3–4 divided treatments. Compared with baseline, the tumor PO₂ was significantly increased in both treatment”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [249] Thrall DE, Maccarini P, Stauffer P, et al. Thermal dose fractionation affects tumour physiological response. Int J Hyperthermia. 2012; 28(5): 431‐ 440. 22804741 PMC3727142

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PV-TS can respond to tumor reduction conditions by releasing NO to inhibit cellular respiration, reducing oxygen consumption and enabling biochemical redistribution of cellular oxygen resources to conserve oxygen.

    “PV‐TS can respond to tumor reduction conditions by releasing NO to inhibit cellular respiration, thereby reducing oxygen consumption and enabling biochemical redistribution of cellular oxygen resources to conserve oxygen.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [281] Yu W, Liu T, Zhang M, et al. O(2) economizer for inhibiting cell respiration to combat the hypoxia obstacle in tumor treatments. ACS Nano. 2019; 13(2): 1784‐ 1794. 30698953

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Margaretten demonstrated that the effect of hyperoxia on lung tumors depends on the oxygen tolerance of lung tumors, and hyperoxia has a more pronounced inhibitory effect on oxygen-sensitive cells.

    “Margaretten demonstrated that the effect of hyperoxia on lung tumors depends on the oxygen tolerance of lung tumors, and hyperoxia has a more pronounced inhibitory effect on oxygen‐sensitive cells.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [295] Margaretten NC, Witschi HR. Effects of hyperoxia on growth of experimental lung metastasis. Carcinogenesis. 1988; 9(3): 433‐ 439. 3345581

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hypoxic tumor cells mainly use glucose to produce glycolytic energy and release lactic acid, which can fuel oxidative metabolism of tumor cells; targeting lactate can selectively kill hypoxic tumor cells.

    “Hypoxic tumor cells mainly use glucose to produce glycolytic energy and release lactic acid, which can fuel the oxidative metabolism of tumor cells. Therefore, targeting lactate can selectively kill hypoxic tumor cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [279] Sonveaux P, Végran F, Schroeder T, et al. Targeting lactate‐fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest. 2008; 118(12): 3930‐ 3942. 19033663 PMC2582933

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Oxidative stress is more pronounced in cancer tissues exposed to hyperoxia than in normal tissues exposed to hyperoxia, and an increase in oxidative stress above the toxicity threshold leads to cancer cell death.

    “This result suggests that oxidative stress is more pronounced in cancer tissues exposed to hyperoxia than in normal tissues exposed to hyperoxia and that an increase in oxidative stress above the toxicity threshold leads to cancer cell death (Figure 4A).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [313] Chopra S, Wallace HM. Induction of spermidine/spermine N1‐acetyltransferase in human cancer cells in response to increased production of reactive oxygen species. Biochem Pharmacol. 1998; 55(7): 1119‐ 1123. 9605436

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The efficacy of anti-VEGF monotherapy in human solid tumors is generally less than satisfactory, with only moderate objective response rates and meaningless survival differences in phase 3 clinical trials.

    “The efficacy of anti‐VEGF monotherapy in human solid tumors is generally less than satisfactory, 267 , 268 with only moderate objective response rates and meaningless survival differences in phase 3 clinical trials.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [267] Batchelor TT, Sorensen AG, di Tomaso E, et al. AZD2171, a pan‐VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell. 2007; 11(1): 83‐ 95. 17222792 PMC2748664 source

      Not checked in the free run.

    • cites [268] Duda DG, Batchelor TT, Willett CG, Jain RK. VEGF‐targeted cancer therapy strategies: current progress, hurdles and future prospects. Trends Mol Med. 2007; 13(6): 223‐ 230. 17462954 PMC2686126

      Not checked in the free run.

    • cites [269] Jain RK, Duda DG, Clark JW, Loeffler JS. Lessons from phase III clinical trials on anti‐VEGF therapy for cancer. Nat Clin Pract Oncol. 2006; 3(1): 24‐ 40. 16407877

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tumor cells showed higher sensitivity to hyperoxia-induced increases in ROS activity, while normal cells were not damaged by ROS due to elevated GSH.

    “Tumor cells showed higher sensitivity to hyperoxia‐induced increases in ROS activity, while normal cells were not damaged by ROS due to elevated GSH.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [312] Allen RG, Balin AK. Effects of oxygen on the antioxidant responses of normal and transformed cells. Exp Cell Res. 2003; 289(2): 307‐ 316. 14499631

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In normal cells, GSH concentration is proportional to ambient oxygen tension; compared with normal cells, tumor cells exhibited higher GSH concentrations under low oxygen tension but were unable to increase GSH with elevated oxygen tension.

    “In normal cells, the GSH concentration is proportional to ambient oxygen tension. Compared with normal cells, tumor cells exhibited higher GSH concentrations under low oxygen tension but were unable to increase GSH with elevated oxygen tension.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [312] Allen RG, Balin AK. Effects of oxygen on the antioxidant responses of normal and transformed cells. Exp Cell Res. 2003; 289(2): 307‐ 316. 14499631

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    3-Bromopyruvate inhibits hexokinase-II activity, thereby inhibiting mitochondrial respiration and glycolysis and reducing mitochondrial oxygen consumption and ATP production.

    “3‐Bromopyruvate inhibits hexokinase‐II activity, thereby inhibiting mitochondrial respiration and glycolysis and reducing mitochondrial oxygen consumption and ATP production.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [280] Zuo L, Nie W, Yu S, et al. Smart tumor‐cell‐derived microparticles provide on‐demand photosensitizer synthesis and hypoxia relief for photodynamic therapy. Angew Chem Int Ed Engl. 2021; 60(48): 25365‐ 25371. 34528355

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Atovaquone reduces the oxygen consumption rate by inhibiting mitochondrial complex III and reducing intratumoral hypoxia.

    “The antimalarial atovaquone is a ubiquitin analog that reduces the oxygen consumption rate (OCR) by inhibiting mitochondrial complex III and reducing intratumoral hypoxia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [275] Ashton TM, Fokas E, Kunz‐Schughart LA, et al. The anti‐malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia. Nat Commun. 2016; 7: 12308. 27453292 PMC4962491

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Antiangiogenic drugs improve tumor blood supply and oxygen content, and vascular normalization provides a new direction for tumor treatment.

    “In conclusion, antiangiogenic drugs improve tumor blood supply and oxygen content, and this idea of vascular normalization provides a new direction for tumor treatment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Human ovarian cancer xenograft mice exposed to HBO (100% oxygen, 2 ATM, 1.5 h) for 21 days had significant reductions in tumor volume, no effect on body weight, and significantly reduced STAT3 (Tyr 705) activation and cyclin-D1 protein/mRNA levels.

    “Human ovarian cancer xenograft mice were exposed to HBO (100% oxygen, 2 ATM, 1.5 h) for 21 days. Mice exposed to HBO had significant reductions in tumor volume, but no effect on body weight was observed. After HBO exposure, STAT3 (Tyr 705) activation and cyclin‐D1 protein/mRNA levels were significantly reduced.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [210] Selvendiran K, Kuppusamy ML, Ahmed S, et al. Oxygenation inhibits ovarian tumor growth by downregulating STAT3 and cyclin‐D1 expressions. Cancer Biol Ther. 2010; 10(4): 386‐ 390. 20562529

      Not checked in the free run.

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

    Premisecitation

    Respiratory hyperoxia increases oxygen saturation in the lungs, increasing oxygen supply to the body.

    “Respiratory hyperoxia increases oxygen saturation in the lungs, increasing oxygen supply to the body.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [284] Ulrich S, Hasler ED, Saxer S, et al. Effect of breathing oxygen‐enriched air on exercise performance in patients with precapillary pulmonary hypertension: randomized, sham‐controlled cross‐over trial. Eur Heart J. 2017; 38(15): 1159‐ 1168. 28329240

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In metastatic CRC, the overall response rate of patients receiving bevacizumab was 3.3%, and in metastatic breast cancer the response rate with bevacizumab alone was 6.7%.

    “In metastatic CRC, the overall response rate of patients receiving bevacizumab (a monoclonal antibody to VEGF) was 3.3%. 270 Similarly, the response rate among patients with metastatic breast cancer treated with the drug alone was 6.7%.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [270] Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007; 25(12): 1539‐ 1544. 17442997 source

      Not checked in the free run.

    • cites [271] Cobleigh MA, Langmuir VK, Sledge GW, et al. A phase I/II dose‐escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol. 2003; 30(5): 117‐ 124. Suppl 16. 14613032

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After hyperoxia, the reduced GSH/oxidized GSH ratio was significantly reduced in both normal and cancer mouse groups; after 24 h of hyperoxia, ROS levels in cancer cells were significantly increased compared with normal cells.

    “Similarly, Kim and co‐workers demonstrated that the reduced GSH/oxidized GSH (GSSG) ratio was significantly reduced after hyperoxia in both normal and cancer mouse groups. After 24 h of hyperoxia, ROS levels in cancer cells were significantly increased compared with those in normal cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [313] Chopra S, Wallace HM. Induction of spermidine/spermine N1‐acetyltransferase in human cancer cells in response to increased production of reactive oxygen species. Biochem Pharmacol. 1998; 55(7): 1119‐ 1123. 9605436

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    EPO levels in hepatoblastoma HepG2 cells treated with 5% O2 and 1% O2 were 2.5 and 4 times higher than in cells treated with 20% O2; hyperoxia (40% O2) significantly inhibited EPO production.

    “The EPO levels in hepatoblastoma HepG2 cells treated with 5% O2 and 1% O2 were 2.5 and 4 times higher than those in cells treated with 20% O2, respectively. In contrast, hyperoxia (40% O2) significantly inhibited EPO production.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [304] Ueno M, Seferynska I, Beckman B, Brookins J, Nakashima J, Fisher JW. Enhanced erythropoietin secretion in hepatoblastoma cells in response to hypoxia. Am J Physiol. 1989; 257(4): C743‐ 9. Pt 1. 2552819

      Not checked in the free run.

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

    Interpretationreasoning

    The results of carbogen respiration were inconsistent, possibly due to inconsistent timing of patients receiving carbogen respiration.

    “Nevertheless, the results of carbogen respiration were inconsistent, which may be due to the inconsistent timing of patients receiving carbogen respiration.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    HBO (2.5 bar, 100% O2, 90 min) had a significant inhibitory effect on tumor growth, and the MAPK pathway was significantly downregulated; an antiangiogenic effect was observed after intermittent HBO treatment.

    “HBO (2.5 bar, 100% O2, 90 min) had a significant inhibitory effect on tumor growth, and the MAPK pathway was significantly downregulated. An antiangiogenic effect was observed after intermittent HBO treatment.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [305] Moen I, Jevne C, Wang J, et al. Gene expression in tumor cells and stroma in dsRed 4T1 tumors in eGFP‐expressing mice with and without enhanced oxygenation. BMC Cancer. 2012; 12: 21. 22251838 PMC3274430

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reduced oxygen tension can induce cancer growth by adapting malignant cells to hypoxia, producing antitumor immunity and maintaining and promoting cancer progression.

    “Multiple reports have suggested that reduced oxygen tension can induce cancer growth by adapting malignant cells to hypoxia, producing antitumor immunity and maintaining and promoting cancer progression.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [46] Niu Y, Lin Z, Wan A, et al. Loss‐of‐function genetic screening identifies Aldolase A as an essential driver for liver cancer cell growth under hypoxia. Hepatology. 2021; 74(3): 1461‐ 1479. 33813748 PMC8518375

      Not checked in the free run.

    • cites [52] Zhang MS, Cui JD, Lee D, et al. Hypoxia‐induced macropinocytosis represents a metabolic route for liver cancer. Nat Commun. 2022; 13(1): 954. 35177645 PMC8854584

      Not checked in the free run.

    • cites [126] Park JH, Kim HJ, Kim CW, et al. Tumor hypoxia represses γδ T cell‐mediated antitumor immunity against brain tumors. Nat Immunol. 2021; 22(3): 336‐ 346. 33574616

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After HBO treatment, elevated intratumoral oxygen tension is retained for a period, making it possible to enhance the tumor/normal tissue oxygenation ratio during radiotherapy.

    “After HBO treatment, the elevated intratumoral oxygen tension is retained for a period of time, making it possible to enhance the tumor/normal tissue oxygenation ratio during radiotherapy. 353 , 354 , 355”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [353] Kinoshita Y, Kohshi K, Kunugita N, Tosaki T, Yokota A. Preservation of tumour oxygen after hyperbaric oxygenation monitored by magnetic resonance imaging. Br J Cancer. 2000; 82(1): 88‐ 92. 10638972 PMC2363207

      Not checked in the free run.

    • cites [354] Kunugita N, Kohshi K, Kinoshita Y, et al. Radiotherapy after hyperbaric oxygenation improves radioresponse in experimental tumor models. Cancer Lett. 2001; 164(2): 149‐ 154. 11179829

      Not checked in the free run.

    • cites [355] Beppu T, Kamada K, Yoshida Y, Arai H, Ogasawara K, Ogawa A. Change of oxygen pressure in glioblastoma tissue under various conditions. J Neurooncol. 2002; 58(1): 47‐ 52. 12160140

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Although respiratory hyperoxia has been shown to be an effective way to eliminate tumor hypoxia, there are obvious limitations to oxygen transport and delivery far from blood vessels in the chaotic TME.

    “Although respiratory hyperoxia has been shown to be an effective way to eliminate tumor hypoxia, there are obvious limitations to oxygen transport and delivery far from blood vessels in the chaotic TME.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Heavy ions can generate an oxygen-containing microenvironment around their orbits due to water ionization; near the Bragg peak region, they can produce abundant oxygen.

    “Additional carbon ions have a synergistic advantage when using flash radiotherapy because heavy ions can generate an oxygen‐containing microenvironment around their orbits due to water ionization; that is, near the end of the carbon ion path (Bragg peak region), they can produce abundant oxygen. 367”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [367] Zakaria AM, Colangelo NW, Meesungnoen J, Azzam EI, Plourde M, Jay‐Gerin JP. Ultra‐High dose‐rate, pulsed (FLASH) radiotherapy with carbon ions: generation of early, transient, highly oxygenated conditions in the tumor environment. Radiat Res. 2020; 194(6): 587‐ 593. 32853343 PMC7856087

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hyperoxia can overcome tumor tissue proliferation and tumor development by alleviating the hypoxic environment, inducing glandular loss, causing DNA damage, and promoting mesenchymal-to-epithelial transition.

    “Hyperoxia can overcome tumor tissue proliferation 321 and the issue of tumor development 322 , 323 , 324 by alleviating the hypoxic environment, inducing glandular loss, causing DNA damage, and promoting mesenchymal‐to‐epithelial transition (MET).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [321] Granowitz EV, Tonomura N, Benson RM, et al. Hyperbaric oxygen inhibits benign and malignant human mammary epithelial cell proliferation. Anticancer Res. 2005; 25(6b): 3833‐ 3842. 16312043

      Not checked in the free run.

    • cites [322] Raa A, Stansberg C, Steen VM, Bjerkvig R, Reed RK, Stuhr LE. Hyperoxia retards growth and induces apoptosis and loss of glands and blood vessels in DMBA‐induced rat mammary tumors. BMC Cancer. 2007; 7: 23. 17263869 PMC1797183

      Not checked in the free run.

    • cites [325] Moen I, Øyan AM, Kalland KH, et al. Hyperoxic treatment induces mesenchymal‐to‐epithelial transition in a rat adenocarcinoma model. PLoS One. 2009; 4(7): e6381. 19636430 PMC2712688

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Hyperoxia is feasible and effective in the treatment of tumors, especially in adjuvant radiotherapy.

    “In conclusion, hyperoxia is feasible and effective in the treatment of tumors, especially in adjuvant radiotherapy.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Hypoxia is an important reason for the poor effect of tumor radiotherapy.
    • Rests on an assumption: Hyperoxia therapy can improve the blood supply to normal tissues to protect and promote the repair of normal tissues.

  • May combine two claims.

    Premisecitation

    Nordsmark applied hyperoxia and carbogen respiration to improve tumor oxygenation, and both carbogen and oxygen inhalation increased tumor PO2 and radiation therapy effectiveness.

    “Nordsmark applied hyperoxia (100% O2) and carbogen respiration (95% O2 + 5% CO2) to improve tumor oxygenation, and the results showed that both carbogen and oxygen inhalation increased tumor PO2 and radiation therapy effectiveness. 349 , 350”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [349] Nordsmark M, Maxwell RJ, Horsman MR, Bentzen SM, Overgaard J. The effect of hypoxia and hyperoxia on nucleoside triphosphate/inorganic phosphate, pO2 and radiation response in an experimental tumour model. Br J Cancer. 1997; 76(11): 1432‐ 1439. 9400939 PMC2228162

      Not checked in the free run.

    • cites [350] Al‐Hallaq HA, River JN, Zamora M, Oikawa H, Karczmar GS. Correlation of magnetic resonance and oxygen microelectrode measurements of carbogen‐induced changes in tumor oxygenation. Int J Radiat Oncol Biol Phys. 1998; 41(1): 151‐ 159. 9588930

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    O2 is a powerful radiosensitizer, which has practical implications for cancer treatment with energetic heavy ions, such as carbon ions.

    “The fact that O2 is a powerful radiosensitizer has practical implications for cancer treatment with energetic heavy ions, such as carbon ions. 366”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [366] Colangelo NW, Azzam EI. The importance and clinical implications of FLASH Ultra‐High Dose‐Rate Studies for Proton and Heavy Ion Radiotherapy. Radiat Res. 2020; 193(1): 1‐ 4. 31657670 PMC6949397

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When radiation is absorbed by biological matter, highly reactive free radicals are produced, and these free radicals ultimately cause tissue damage.

    “When radiation is absorbed by biological matter, highly reactive free radicals are produced, and these free radicals ultimately cause tissue damage.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [339] Henk JM, Kunkler PB, Smith CW. Radiotherapy and hyperbaric oxygen in head and neck cancer. Final report of first controlled clinical trial. Lancet. 1977; 2(8029): 101‐ 103. 69191

      Not checked in the free run.

    • cites [340] Henk JM, Smith CW. Radiotherapy and hyperbaric oxygen in head and neck cancer. Interim report of second clinical trial. Lancet. 1977; 2(8029): 104‐ 105. 69192

      Not checked in the free run.

    • cites [341] Wildermuth O. The case for hyperbaric oxygen radiotherapy. JAMA. 1965; 191: 986‐ 990. 14257742

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Respiratory hyperoxia can alleviate tumor hypoxia and inhibit tumor progression through various mechanisms.

    “Respiratory hyperoxia can alleviate tumor hypoxia and inhibit tumor progression through various mechanisms (Table 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Tumor cells near the oxygen diffusion limit exhibit improved survival under subnormal oxygen stress conditions, making them resistant to radiation therapy.

    “These findings suggest that tumor cells near the oxygen diffusion limit exhibit improved survival under subnormal oxygen stress conditions, making them resistant to radiation therapy.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Under hyperoxia, the partial pressure of oxygen in tissues is more than 10 times that under normoxia, which can greatly improve the hypoxic state of tumors and enhance the effect of radiotherapy.

    “Under hyperoxia, the partial pressure of oxygen in tissues is more than 10 times that under normoxia, which can greatly improve the hypoxic state of tumors and enhance the effect of radiotherapy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    HBOT dissolves oxygen in plasma and improves oxygen supply to hypoxic tumor cells.

    “HBOT, which uses oxygen as a therapeutic, dissolves oxygen in plasma and has been found to improve oxygen supply to hypoxic tumor cells, a treatment that has been used in conjunction with radiation therapy to treat malignancies. 352”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [352] Hartmann KA, van der Kleij AJ, Carl UM, Hulshof MC, Willers R, Sminia P. Effects of hyperbaric oxygen and normobaric carbogen on the radiation response of the rat rhabdomyosarcoma R1H. Int J Radiat Oncol Biol Phys. 2001; 51(4): 1037‐ 1044. 11704328

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hyperoxia exposure (95% O2, 40-64 h) induces cyclin-dependent kinase 2 activity and acute inhibition of DNA synthesis; the S-phase block also has different degrees of blockade in the G1 and G2 phases.

    “Hyperoxia exposure (95% O2, 40–64 h) induces cyclin‐dependent kinase 2 activity and acute inhibition of DNA synthesis. The S‐phase block also has different degrees of blockade in the G1 and G2 phases (Figure 4C).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [316] Bilodeau JF, Faure R, Piedboeuf B, Mirault ME. Hyperoxia induces S‐phase cell‐cycle arrest and p21(Cip1/Waf1)‐independent Cdk2 inhibition in human carcinoma T47D‐H3 cells. Exp Cell Res. 2000; 256(2): 347‐ 357. 10772807

      Not checked in the free run.

    • cites [317] Helt CE, Rancourt RC, Staversky RJ, O'Reilly MA. p53‐dependent induction of p21(Cip1/WAF1/Sdi1) protects against oxygen‐induced toxicity. Toxicol Sci. 2001; 63(2): 214‐ 222. 11568365

      Not checked in the free run.

    • cites [318] Gehen SC, Vitiello PF, Bambara RA, Keng PC, O'Reilly MA. Downregulation of PCNA potentiates p21‐mediated growth inhibition in response to hyperoxia. Am J Physiol Lung Cell Mol Physiol. 2007; 292(3): L716‐ 24. 17085526

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    According to current studies, respiratory hyperoxia has inhibitory effects on lung tumors and other tumor types, with no significant difference in effect.

    “According to current studies, respiratory hyperoxia has inhibitory effects on lung tumors and other tumor types, with no significant difference in effect.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Flash radiotherapy using carbon ions, which are more toxic to the tumor, can significantly improve treatment.

    “This suggests that flash radiotherapy using carbon ions, which are more toxic to the tumor, can significantly improve treatment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    FLASH radiotherapy applies radiation at an ultrahigh dose rate several orders of magnitude higher than current clinical routine radiotherapy, which can make normal tissues resistant due to abnormal hypoxia while still maintaining local tumor control.

    “FLASH radiotherapy applies radiation at an ultrahigh dose rate several orders of magnitude higher than the current clinical routine radiotherapy, which can make normal tissues resistant due to abnormal hypoxia while still maintaining local tumor control. 362”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [362] Hughes JR, Parsons JL. FLASH radiotherapy: current knowledge and future insights using proton‐beam therapy. Int J Mol Sci. 2020; 21(18):6492. PMC7556020 32899466

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Erythrocyte membrane-encapsulated perfluorocarbon particles have efficient oxygen loading and deliver oxygen into solid tumors, facilitating radiotherapy-based cancer therapy.

    “Recently, developed erythrocyte membrane‐encapsulated perfluorocarbon particles were shown to have fairly efficient oxygen loading and to efficiently deliver oxygen into solid tumors, facilitating radiotherapy‐based cancer therapy. 344”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [344] Gao M, Liang C, Song X, et al. Erythrocyte‐membrane‐enveloped perfluorocarbon as nanoscale artificial red blood cells to relieve tumor hypoxia and enhance cancer radiotherapy. Adv Mater. 2017; 29(35). 28722140

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Hyperoxia therapy does not promote tumorigenesis but enhances the effect of radiotherapy.

    “However, a large number of basic and clinical studies have found that hyperoxia therapy not only does not promote tumorigenesis but enhances the effect of radiotherapy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In 1953, Gray and colleagues showed that radiation sensitivity was dependent on oxygen concentration and that the effectiveness of X-ray therapy might be enhanced if cancer patients breathed oxygen while being irradiated.

    “However, it was not until 1953 that Gray and colleagues had an open‐label study showing that radiation sensitivity was dependent on oxygen concentration and that the effectiveness of X‐ray therapy might be enhanced if cancer patients were breathing oxygen while being irradiated.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [333] Gray LH, Conger AD, Ebert M, Hornsey S, Scott OC. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol. 1953; 26(312): 638‐ 648. 13106296 source

      Not checked in the free run.

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

    Premisecitation

    Thomlinson and Gray proposed that hypoxia may be central to human tumors and is a major culprit of radiotherapy resistance.

    “Just 2 years later, Thomlinson and Gray proposed that hypoxia may be central to human tumors and is a major culprit of radiotherapy resistance.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [334] Thomlinson RH, Gray LH. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer. 1955; 9(4): 539‐ 549. 13304213 PMC2073776

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nanoparticles generate oxygen in hypoxic regions of tumors through oxygen-carrying/oxygenation without any oxygen toxicity to other tissues and organs.

    “Nanoparticles generate oxygen in hypoxic regions of tumors through oxygen‐carrying/oxygenation without any oxygen toxicity to other tissues and organs. 356”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [356] Xie J, Gong L, Zhu S, Yong Y, Gu Z, Zhao Y. Emerging strategies of nanomaterial‐mediated tumor radiosensitization. Adv Mater. 2019; 31(3): e1802244. 30156333

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Respiratory hyperoxia can inhibit the generation of G-MDSC exosomes, reduce the stemness of CRC cells and inhibit the development of CRC.

    “Respiratory hyperoxia can inhibit the generation of G‐MDSC exosomes, reduce the stemness of CRC cells and inhibit the development of CRC (Figure 7). 412”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [412] Wang Y, Yin K, Tian J, et al. Granulocytic myeloid‐derived suppressor cells promote the stemness of colorectal cancer cells through exosomal S100A9. Adv Sci. 2019; 6(18): 1901278. PMC6755519 31559140

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HBO further enhances antitumor efficacy by increasing oxygen tension, reducing collagen deposition in the tumor ECM, promoting the penetration and accumulation of DOX liposomes into tumors, and increasing the sensitivity of tumor cells to DOX liposomes.

    “HBO further enhances antitumor efficacy by increasing oxygen tension, reducing collagen deposition in the tumor ECM, promoting the penetration and accumulation of DOX liposomes into tumors, and increasing the sensitivity of tumor cells to DOX liposomes. 389 , 390”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [389] Moen I, Tronstad KJ, Kolmannskog O, Salvesen GS, Reed RK, Stuhr LE. Hyperoxia increases the uptake of 5‐fluorouracil in mammary tumors independently of changes in interstitial fluid pressure and tumor stroma. BMC Cancer. 2009; 9: 446. 20017908 PMC2805681

      Not checked in the free run.

    • cites [390] Wu X, Zhu Y, Huang W, et al. Hyperbaric oxygen potentiates doxil antitumor efficacy by promoting tumor penetration and sensitizing cancer cells. Adv Sci. 2018; 5(8): 1700859. PMC6097095 30128223

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Clinical studies have shown that only 30% and 40% of melanoma patients benefit from PD-1 inhibitors, and PD-1 blockade therapy is ineffective in most patients.

    “However, clinical studies have shown that only 30% and 40% of melanoma patients benefit from PD‐1 inhibitors, and PD‐1 blockade therapy is ineffective in most patients. 414 , 415 , 416”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [414] Hussain SA, Birtle A, Crabb S, et al. From clinical trials to real‐life clinical practice: the role of immunotherapy with PD‐1/PD‐L1 inhibitors in advanced urothelial carcinoma. Eur Urol Oncol. 2018; 1(6): 486‐ 500. 31158093

      Not checked in the free run.

    • cites [415] Najjar YG, Menk AV, Sander C, et al. Tumor cell oxidative metabolism as a barrier to PD‐1 blockade immunotherapy in melanoma. JCI Insight. 2019; 4(5):e124989. PMC6483505 30721155

      Not checked in the free run.

    • cites [416] Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti‐PD‐1 antibody in cancer. N Engl J Med. 2012; 366(26): 2443‐ 2454. 22658127 PMC3544539 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Stephen demonstrated that combined immunotherapy with respiratory hyperoxia can reduce tumor hypoxia and attenuate hypoxic/HIF-1α/A2 adenosine immunosuppression, thereby exerting a powerful antitumor effect.

    “Stephen demonstrated that combined immunotherapy with respiratory hyperoxia can reduce tumor hypoxia and attenuate hypoxic/HIF‐1α/A2 adenosine immunosuppression, thereby exerting a powerful antitumor effect. 306”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [306] Hatfield SM, Sitkovsky MV. Antihypoxic oxygenation agents with respiratory hyperoxia to improve cancer immunotherapy. J Clin Invest. 2020; 130(11): 5629‐ 5637. 32870821 PMC7598059

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hyperoxia inhibits the dedifferentiation process, promotes the differentiation of GSCs, and increases the sensitivity of glioma cells to chemotherapy.

    “Hyperoxia inhibits the dedifferentiation process, promotes the differentiation of GSCs, and increases the sensitivity of glioma cells to chemotherapy. 14”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Wang P, Wan W, Xiong S, et al. HIF1α regulates glioma chemosensitivity through the transformation between differentiation and dedifferentiation in various oxygen levels. Sci Rep. 2017; 7(1): 7965. 28801626 PMC5554160

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In triple-negative breast cancer, 60% O2 can reduce the secretion of exosomes from MDSCs caused by hypoxia and inhibit the upregulation of PD-L1 protein expression.

    “In triple‐negative breast cancer, 60% O2 can not only reduce the secretion of exosomes from MDSCs caused by hypoxia but can also inhibit the upregulation of PD‐L1 protein expression. 422”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [422] Qian X, Zhang Q, Shao N, et al. Respiratory hyperoxia reverses immunosuppression by regulating myeloid‐derived suppressor cells and PD‐L1 expression in a triple‐negative breast cancer mouse model. Am J Cancer Res. 2019; 9(3): 529‐ 545. 30949408 PMC6448063

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Experimental results demonstrated that HBO increases blood vessel density in large tumors, such as in epithelial ovarian cancer, and mice treated with cisplatin and HBO showed significantly delayed tumor growth compared with mice treated with cisplatin alone.

    “The experimental results demonstrated that HBO increases blood vessel density in large tumors, such as in epithelial ovarian cancer, and mice treated with cisplatin and HBO showed significantly delayed tumor growth compared with mice treated with cisplatin alone.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [382] Alagoz T, Buller RE, Anderson B, et al. Evaluation of hyperbaric oxygen as a chemosensitizer in the treatment of epithelial ovarian cancer in xenografts in mice. Cancer. 1995; 75(9): 2313‐ 2322. 7536123

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    miR-210 is a highly upregulated miRNA in hypoxic cells and may serve as an in vivo marker of tumor hypoxia.

    “Studies have reported that miR‐210 is a highly upregulated miRNA in hypoxic cells and may serve as an in vivo marker of tumor hypoxia. 405 , 406”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [405] Huang X, Ding L, Bennewith KL, et al. Hypoxia‐inducible mir‐210 regulates normoxic gene expression involved in tumor initiation. Mol Cell. 2009; 35(6): 856‐ 867. 19782034 PMC2782615

      Not checked in the free run.

    • cites [406] Fasanaro P, D'Alessandra Y, Di Stefano V, et al. MicroRNA‐210 modulates endothelial cell response to hypoxia and inhibits the receptor tyrosine kinase ligand Ephrin‐A3. J Biol Chem. 2008; 283(23): 15878‐ 15883. 18417479 PMC3259646 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High concentrations of adenosine impair the activation and function of T cells and NK cells and enhance the function of Tregs and the differentiation of M2 macrophages, resulting in strong immunosuppression.

    “High concentrations of adenosine impair the activation and function of T cells and NK cells and enhance the function of Tregs and the differentiation of M2 macrophages, resulting in strong immunosuppression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [206] Hatfield SM, Kjaergaard J, Lukashev D, et al. Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci Transl Med. 2015; 7(277): 277ra30. PMC4641038 25739764

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hypoxia promotes the accumulation of PMNs inside tumors but then alters their phenotype in situ, limiting their ability to directly inhibit tumor growth.

    “Hypoxia promotes the accumulation of PMNs inside tumors but then alters their phenotype in situ, limiting their ability to directly inhibit tumor growth.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [411] Mahiddine K, Blaisdell A, Ma S, Créquer‐Grandhomme A, Lowell CA, Erlebacher A. Relief of tumor hypoxia unleashes the tumoricidal potential of neutrophils. J Clin Invest. 2020; 130(1): 389‐ 403. 31600172 PMC6934192

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hypoxia inhibited the activities of KDM3A and KDM5C and reduced ROS production and tumor cell apoptosis.

    “Hypoxia inhibited the activities of KDM3A and KDM5C and reduced ROS production and tumor cell apoptosis. 403 , 404”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [403] Qian X, Li X, Shi Z, et al. KDM3A senses oxygen availability to regulate PGC‐1α‐mediated mitochondrial biogenesis. Mol Cell. 2019; 76(6): 885‐ 895.e7. 31629659

      Not checked in the free run.

    • cites [404] Li J, Zhang T, Ren T, et al. Oxygen‐sensitive methylation of ULK1 is required for hypoxia‐induced autophagy. Nat Commun. 2022; 13(1): 1172. 35246531 PMC8897422

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In noncancerous hypoxic tissues, such as normal tissues after irradiation, HBO significantly increases oxygenation and promotes angiogenesis, ultimately leading to increased blood flow.

    “In noncancerous hypoxic tissues, such as normal tissues after irradiation, HBO significantly increases oxygenation and promotes angiogenesis, ultimately leading to increased blood flow. 381”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [381] Marx RE, Ehler WJ, Tayapongsak P, Pierce LW. Relationship of oxygen dose to angiogenesis induction in irradiated tissue. Am J Surg. 1990; 160(5): 519‐ 524. 2240387

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hyperoxia (60% O2) upregulates MHC expression, confirming that MHC antigen presentation regulation is oxygen-dependent.

    “while hyperoxia (60% O2) upregulates MHC expression, confirming that MHC antigen presentation regulation is oxygen‐dependent. 420”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [420] Sethumadhavan S, Silva M, Philbrook P, et al. Hypoxia and hypoxia‐inducible factor (HIF) downregulate antigen‐presenting MHC class I molecules limiting tumor cell recognition by T cells. PLoS One. 2017; 12(11): e0187314. 29155844 PMC5695785

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HIF reduces the expression of MHC I while increasing the expression of PD-L1, thereby reducing the tumor cell killing ability of cytotoxic T lymphocytes.

    “For example, HIF reduces the expression of major histocompatibility complex I (MHC I) while increasing the expression of PD‐L1, thereby reducing the tumor cell killing ability of cytotoxic T lymphocytes (CTLs), 418 , 419”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [418] Chouaib S, Noman MZ, Kosmatopoulos K, Curran MA. Hypoxic stress: obstacles and opportunities for innovative immunotherapy of cancer. Oncogene. 2017; 36(4): 439‐ 445. 27345407 PMC5937267

      Not checked in the free run.

    • cites [419] Noman MZ, Buart S, Romero P, et al. Hypoxia‐inducible miR‐210 regulates the susceptibility of tumor cells to lysis by cytotoxic T cells. Cancer Res. 2012; 72(18): 4629‐ 4641. 22962263

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After the remission of hypoxia in respiratory hyperoxia, the tumor suppressor effect of PMNs was enhanced, resulting in a reduction in tumor burden despite reduced PMN infiltration.

    “After the remission of hypoxia in respiratory hyperoxia, the tumor suppressor effect of PMNs was enhanced, resulting in a reduction in tumor burden despite reduced PMN infiltration. 411”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [411] Mahiddine K, Blaisdell A, Ma S, Créquer‐Grandhomme A, Lowell CA, Erlebacher A. Relief of tumor hypoxia unleashes the tumoricidal potential of neutrophils. J Clin Invest. 2020; 130(1): 389‐ 403. 31600172 PMC6934192

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hyperoxia leads to dysregulation of protein folding, which in turn induces apoptosis mediated by the unfolded protein response.

    “Experimental results showed that hyperoxia leads to dysregulation of protein folding, which in turn induces apoptosis mediated by the unfolded protein response.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [398] Lee D, Sun S, Ho AS, et al. Hyperoxia resensitizes chemoresistant glioblastoma cells to temozolomide through unfolded protein response. Anticancer Res. 2014; 34(6): 2957‐ 2966. 24922660

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hypoxia is a potent determinant of the tumor-associated PMN phenotype and directly affects PMN-tumor cell interactions.

    “Mahiddine reported that hypoxia is a potent determinant of the tumor‐associated PMN phenotype and directly affects PMN‐tumor cell interactions.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [411] Mahiddine K, Blaisdell A, Ma S, Créquer‐Grandhomme A, Lowell CA, Erlebacher A. Relief of tumor hypoxia unleashes the tumoricidal potential of neutrophils. J Clin Invest. 2020; 130(1): 389‐ 403. 31600172 PMC6934192

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hypoxia severely hinders various anticancer strategies and is a major driver of the development of tumor resistance, invasion, and metastasis.

    “Hypoxia severely hinders various anticancer strategies and is also a major driver of the development of tumor resistance, invasion, and metastasis. 460”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [460] He G, Peng X, Wei S, et al. Exosomes in the hypoxic TME: from release, uptake and biofunctions to clinical applications. Mol Cancer. 2022; 21(1): 19. 35039054 PMC8762953

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    Increasing oxygen supply to the tumor can return tumor cells to their normal state and thus resensitize them to existing therapies.

    “increasing oxygen supply to the tumor can return tumor cells to their normal state and thus resensitize them to existing therapies.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Tumors thrive in the absence of oxygen and resist treatment.

  • May combine two claims.

    Premisecitation

    The main reasons for the significant oxygen effects observed in other studies are the presence of hypoxic cells in solid tumors and the simultaneous occurrence of light and oxidation.

    “The main reasons for the significant oxygen effects observed in other studies are the presence of hypoxic cells in solid tumors and the simultaneous occurrence of light and oxidation. 439”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [439] Henderson BW, Fingar VH. Oxygen limitation of direct tumor cell kill during photodynamic treatment of a murine tumor model. Photochem Photobiol. 1989; 49(3): 299‐ 304. 2525260

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the clinical treatment of advanced pleural malignant mesothelioma, additional PDT/HBO is a safe and technically feasible approach.

    “Additionally, in the clinical treatment of advanced pleural malignant mesothelioma, investigators demonstrated that additional PDT/HBO is a safe and technically feasible approach (Table 3). 454 , 455”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [454] Matzi V, Maier A, Sankin O, et al. Photodynamic therapy enhanced by hyperbaric oxygenation in palliation of malignant pleural mesothelioma: clinical experience. Photodiagnosis Photodyn Ther. 2004; 1(1): 57‐ 64. 25048065

      Not checked in the free run.

    • cites [455] Matzi V, Maier A, Woltsche M, Smolle‐Jüttner FM. Polyhematoporphyrin‐mediated photodynamic therapy and decortication in palliation of malignant pleural mesothelioma: a clinical pilot study. Interact Cardiovasc Thorac Surg. 2004; 3(1): 52‐ 56. 17670175

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HBO disrupts hypoxia-mediated immunosuppression and helps PD-1 Ab trigger robust cytotoxic T lymphocyte responses and durable immune memory to suppress tumor recurrence.

    “Furthermore, HBO disrupts hypoxia‐mediated immunosuppression and helps PD‐1 Ab trigger robust cytotoxic T lymphocyte responses and durable immune memory to suppress tumor recurrence. 423 , 424”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [423] Liu X, Ye N, Liu S, et al. Hyperbaric oxygen boosts PD‐1 antibody delivery and T cell infiltration for augmented immune responses against solid tumors. Adv Sci. 2021; 8(15): e2100233. PMC8336507 34085419

      Not checked in the free run.

    • cites [424] Herrera‐Campos AB, Zamudio‐Martinez E, Delgado‐Bellido D, et al. Implications of hyperoxia over the tumor microenvironment: an overview highlighting the importance of the immune system. Cancers. 2022; 14(11):2740. PMC9179641 35681719

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Tumors that grow in hypoxic environments are more metastatic and more lethal to patients.

    “Tumors that grow in hypoxic environments are known to be more metastatic and more lethal to patients.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Improving tumor tissue oxygenation can increase the oxygen content in tumor tissue and the content of singlet oxygen, which can improve the efficiency of PDT.

    “Therefore, improving tumor tissue oxygenation can increase the oxygen content in tumor tissue and the content of singlet oxygen (the excited state of ordinary oxygen, which is a type of ROS), which can improve the efficiency of PDT. 432”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [432] Jiang W, Zhang Z, Wang Q, et al. Tumor reoxygenation and blood perfusion enhanced photodynamic therapy using ultrathin graphdiyne oxide nanosheets. Nano Lett. 2019; 19(6): 4060‐ 4067. 31136712

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The cytotoxicity of porphyrin and its related substances (photosensitizers) is mainly mediated by singlet oxygen, while hypoxic cells are less affected by porphyrin and light.

    “Studies have shown that the cytotoxicity of porphyrin and its related substances (photosensitizers) is mainly mediated by singlet oxygen, while hypoxic cells are less affected by porphyrin and light. 223”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [223] Liang X, Chen M, Bhattarai P, Hameed S, Dai Z. Perfluorocarbon@Porphyrin nanoparticles for tumor hypoxia relief to enhance photodynamic therapy against liver metastasis of colon cancer. ACS Nano. 2020; 14(10): 13569‐ 13583. 32915537

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hypoxic cells are resistant to PDT treatment, and without oxygen, PDT has no cell-killing effect.

    “Hypoxic cells are resistant to PDT treatment, and without oxygen, PDT has no cell‐killing effect.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [433] Chen Q, Huang Z, Chen H, Shapiro H, Beckers J, Hetzel FW. Improvement of tumor response by manipulation of tumor oxygenation during photodynamic therapy. Photochem Photobiol. 2002; 76(2): 197‐ 203. 12194217

      Not checked in the free run.

    • cites [434] Dong GC, Hu SX, Zhao GY, Gao SZ, Wu LR. Experimental study on cytotoxic effects of hyperbaric oxygen and photodynamic therapy on mouse transplanted tumor. Chin Med J. 1987; 100(9): 697‐ 702. 2964998

      Not checked in the free run.

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

    Interpretationreasoning

    Improving oxygenation can remove hypoxia-stimulated vascular malformations and degrade the dense ECM of tumor cells, improving drug delivery to hypoxic areas of tumors.

    “Theoretically, the application of hyperoxia therapy in tumor therapy is justified for the following reasons: improving oxygenation can remove hypoxia‐stimulated vascular malformations and degrade the dense ECM of tumor cells, improving drug delivery to hypoxic areas of tumors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In patients with advanced esophageal cancer, tumor length was reduced in both PDT and PDT/HBO groups, and tumor reduction was more pronounced in the PDT/HBO group.

    “Tumor length was reduced in both groups, and the tumor reduction was more pronounced in the PDT/HBO group. The 12‐month survival rate was 28.6% in the PDT group and 41.2% in the PDT/HBO group. 451”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [451] Maier A, Anegg U, Tomaselli F, et al. Does hyperbaric oxygen enhance the effect of photodynamic therapy in patients with advanced esophageal carcinoma? A clinical pilot study. Endoscopy. 2000; 32(1): 42‐ 48. 10691271

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Improved oxygenation also recruits immune cells to the tumor or enhances the antitumor ability of immune cells.

    “Improved oxygenation also recruits immune cells to the tumor or enhances the antitumor ability of immune cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    This process requires oxygen molecules, and ROS can induce apoptosis or necrosis, microvascular damage, and immune responses.

    “This process requires oxygen molecules, and ROS can induce apoptosis or necrosis, microvascular damage, and immune responses. 428 , 429 , 430”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [428] Dougherty TJ, Gomer CJ, Henderson BW, et al. Photodynamic therapy. J Natl Cancer Inst. 1998; 90(12): 889‐ 905. 9637138 PMC4592754

      Not checked in the free run.

    • cites [429] Dalla Via L, Marciani Magno S. Photochemotherapy in the treatment of cancer. Curr Med Chem. 2001; 8(12): 1405‐ 1418. 11562274

      Not checked in the free run.

    • cites [430] Fan W, Huang P, Chen X. Overcoming the Achilles' heel of photodynamic therapy. Chem Soc Rev. 2016; 45(23): 6488‐ 6519. 27722560

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Although the antitumor effect of hyperoxia therapy is weak, it may improve the effectiveness of some therapies and be beneficial as an adjuvant in cancer treatment.

    “With these facts in mind, although the antitumor effect of hyperoxia therapy is weak, it may improve the effectiveness of some therapies and be beneficial as an adjuvant in cancer treatment.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Hypoxia is an important reason for the poor effect of tumor radiotherapy.
    • Rests on an assumption: Hyperoxia therapy can improve the blood supply to normal tissues to protect and promote the repair of normal tissues.

  • May combine two claims.

    Interpretationreasoning

    The improvement in oxygenation causes cells to enter a proliferative phase, which makes them sensitive to radiation therapy and certain chemotherapeutic agents.

    “The improvement in oxygenation causes cells to enter a proliferative phase, which makes them sensitive to radiation therapy and certain chemotherapeutic agents.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Combined PDT/HBO effectively and rapidly reduces intraluminal tumor burden and helps regulate further treatment procedures in patients.

    “Combined PDT/HBO effectively and rapidly reduces intraluminal tumor burden and helps regulate further treatment procedures in patients. 452 , 453”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [452] Tomaselli F, Maier A, Sankin O, et al. Acute effects of combined photodynamic therapy and hyperbaric oxygenation in lung cancer–a clinical pilot study. Lasers Surg Med. 2001; 28(5): 399‐ 403. 11413551

      Not checked in the free run.

    • cites [453] Tomaselli F, Maier A, Pinter H, Stranzl H, Smolle‐Jüttner FM. Photodynamic therapy enhanced by hyperbaric oxygen in acute endoluminal palliation of malignant bronchial stenosis (clinical pilot study in 40 patients). Eur J Cardiothorac Surg. 2001; 19(5): 549‐ 554. 11343929

      Not checked in the free run.

111 of 111

  • The paper relies on this without support.

    Excess hydrogen peroxide exists in the hypoxic microenvironment of tumors and greatly limits the efficacy of tumor therapy.

    “Excess hydrogen peroxide (H2O2) exists in the hypoxic microenvironment of tumors, which greatly limits the efficacy of tumor therapy.”

  • The paper relies on this without support.

    Cellular respiration is the main process by which living cells consume oxygen.

    “Cellular respiration is the main process by which living cells consume oxygen.”

  • The paper relies on this without support.

    Hypoxia is an important reason for the poor effect of tumor radiotherapy.

    “Hypoxia is an important reason for the poor effect of tumor radiotherapy.”

  • The paper relies on this without support.

    Hyperoxia therapy can improve the blood supply to normal tissues to protect and promote the repair of normal tissues.

    “Hyperoxia therapy can improve the blood supply to normal tissues to protect and promote the repair of normal tissues.”

  • The paper relies on this without support.

    Tumors thrive in the absence of oxygen and resist treatment.

    “Tumors thrive in the absence of oxygen and resist treatment”

  • The paper relies on this without support.

    Currently, hyperoxia is often used as adjunctive therapy for patients with advanced cancer, which reduces the antitumor efficacy of hyperoxia.

    “Currently, hyperoxia is often used as adjunctive therapy for patients with advanced cancer, which reduces the antitumor efficacy of hyperoxia.”

  • The paper relies on this without support.

    Oxygen poisoning occurs with excess oxygen concentrations and oxygen inhalation times.

    “Oxygen poisoning occurs with excess oxygen concentrations and oxygen inhalation times.”

  • The paper relies on this without support.

    Every tissue, disease state, and individual has an optimal oxygen level.

    “Every tissue, disease state, and individual has an optimal oxygen level.”

  • The paper relies on this without support.

    Mismatches in oxygen supply and demand can lead to pathological changes.

    “Mismatches in oxygen supply and demand can lead to pathological changes”

  • The paper relies on this without support.

    Hyperoxia can recruit immune cells, such as T and NK cells.

    “Hyperoxia can recruit immune cells, such as T and NK cells”

  • The paper relies on this without support.

    One of the most important and basic effects of hyperoxia is to activate ROS, which kills tumor cells by damaging mitochondria.

    “One of the most important and basic effects of hyperoxia is to activate ROS, which kills tumor cells by damaging mitochondria.”
11 of 11

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?

  • Radiopharmaceuticals can provide precise and early diagnostic information, leading to more targeted and effective treatment strategies, which may reduce overall healthcare costs by minimizing unnecessary interventions and enhancing treatment success rates.

    “Radiopharmaceuticals, particularly in the context of nuclear medicine procedures, can provide precise and early diagnostic information, leading to more targeted and effective treatment strategies. This, in turn, may result in reduced overall healthcare costs by minimizing unnecessary interventions and enhancing treatment success rates [127].”

    From Radiopharmaceuticals: navigating the frontier of precision medicine and therapeutic innovation (2024) · cites this paper as [127]

    Split into 2 atoms — 0 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 2 unverifiable. Expand the claim to see per-atom verdicts.

    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.

  • Opposite effects on CDK2 activity

    Minor

    The text says hyperoxia induces CDK2 activity, while the Figure 4 caption says it severely inhibits that activity.

  • Figure 5 switches from radiotherapy to chemotherapy

    Minor

    Figure 5 is identified as a diagram of hyperoxia-assisted radiation therapy, but its caption concludes that the depicted mechanism promotes chemotherapy.

  • Reference 210 has conflicting author and year information

    Minor

    Table 2 attributes reference 210 to a 2011 study by Karuppaiyah and colleagues, whereas the reference list identifies it as a 2010 study by Selvendiran and colleagues.

3 of 3

Cites

4 retracted

Flagged first, then by citations

2 of the 468 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. 10.1038/s41467-022-31764-9 · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Zhuang, Y., Liu, K., He, Q., Gu, X., Jiang, C., & Wu, J.
Affiliations
  • State Key Laboratory of Pharmaceutical Biotechnology (CN)
  • Microecological, Regenerative and Microfabrication Technical Platform for Biomedicine and Tissue Engineering Jinan Microecological Biomedicine Shandong Laboratory Jinan City China
Corresponding author
  • Jiang, Chunping
  • Wu, Junhua
ORCID
Venue
MedComm
Publisher
Wiley
Published
2023-01-23
Volume
4
Issue
1
Pages
e203-e203
ISSN
2688-2663 (ISSN-L)
DOI
10.1002/mco2.203
PMC
PMC9870816
OpenAlex
W4317790174
Cited by
119
References
468
Citations by year
2026: 31 · 2025: 47 · 2024: 28 · 2023: 13
FWCI
3.76
Type
journal article
Language
en
Open access
Licence
Locations
  • MedComm (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (81972888, 82272819)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
tumor hypoxia, hypoxia signaling, solid tumors, tumor microenvironment, cancer metabolism, antitumor immunity, tumor angiogenesis, hypoxia-targeted therapy, radiotherapy resistance, chemoresistance, immunotherapy resistance, tumor oxygenation

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 2026-10-10.

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

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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