The regulation of immune checkpoints by the hypoxic tumor microenvironment

Hu, Min; Li, Yongfu; Lu, Yuting; Wang, Miao; Li, Yingrui; Wang, Chaoying; Li, Qin; Zhao, Hong

doi:10.7717/peerj.11306

Cited by 51Cancer Immunotherapy and BiomarkersCancer, Hypoxia, and MetabolismAdenosine and Purinergic Signaling

The regulation of immune checkpoints by the hypoxic tumor microenvironment

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Hu, Min, Li, Yongfu, Lu, Yuting, Wang, Miao, Li, Yingrui, Wang, Chaoying, Li, Qin, Zhao, Hong·2021·PeerJ

DOI 10.7717/peerj.11306PMC PMC8109006

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Abstract

The tumor microenvironment (TME) influences the occurrence and progression of tumors, and hypoxia is an important characteristic of the TME. The expression of programmed death 1 (PD1)/programmed death-ligand 1 (PDL1), cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), and other immune checkpoints in hypoxic malignant tumors is often significantly increased, and is associated with poor prognosis. The application of immune checkpoint inhibitors (ICIs) for treating lung cancer, urothelial carcinoma, and gynecological tumors has achieved encouraging efficacy; however, the rate of efficacy of ICI single-drug treatment is only about 20%. In the present review, we discuss the possible mechanisms by which the hypoxic TME regulates immune checkpoints. By activating hypoxia-inducible factor-1α(HIF-1α), regulating the adenosine (Ado)-A2aR pathway, regulating the glycolytic pathway, and driving epithelial-mesenchymal transition (EMT) and other biological pathways, hypoxia regulates the expression levels of CTLA4, PD1, PDL1, CD47, lymphocyte activation gene 3 (LAG3), T-cell immunoglobulin and mucin domain 3 (TIM3), and other immune checkpoints, which interfere with the immune effector cell anti-tumor response and provide convenient conditions for tumors to escape immune surveillance. The combination of HIF-1αinhibitors, Ado-inhibiting tumor immune microenvironment regulatory drugs, and other drugs with ICIs has good efficacy in both preclinical studies and phase I-II clinical studies. Exploring the effects of TME hypoxia on the expression of immune checkpoints and the function of infiltrating immune cells has greatly clarified the relationship between the hypoxic TME and immune escape, which is of great significance for the development of new drugs and the search for predictive markers of the efficacy of immunotherapy for treating malignant tumors. In the future, combination therapy with hypoxia pathway inhibitors and ICIs may be an effective anti-tumor treatment strategy.

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Hypoxia has been shown to modulate the expression of immune checkpoints such as CTLA-4, CD47, PD-1/L-1, and TIM3 in order to manipulate immune cells' mediated anti-tumour response, thereby inhibiting immune surveillance.
“Hypoxia has been shown to modulate the expression of immune checkpoints such as CTLA-4, CD47, PD-1/L-1, and TIM3 in order to manipulate immune cells’ mediated anti-tumour response, thereby inhibiting immune surveillance [126].”
From Immune Checkpoint Inhibitors in Cancer Therapy (2022) · cites this paper as [126]

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Immunogenic cell death
Garg, A. D., Dudek-Perić, A. M., Romano, E., & Agostinis, P. (2015) · The International Journal of Developmental Biology · doi:10.1387/ijdb.150061pa · Cited by 244 · cited 2× · see citing works
“As a result, autophagy stimulates the body’s immune response to tumor and kills tumor cells, namely immunogenic cell death (ICD) (Garg et al., 2015) .”
Background
Antimetastatic Effects of Blocking PD-1 and the Adenosine A2A Receptor
Mittal, D., Young, A., Stannard, K. A., Yong, M. C. R., Teng, M. W. L., Allard, B., Stagg, J., & Smyth, M. J. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0957 · Cited by 243 · cited 1× · see citing works
“Some studies have shown that the combination of A2a antagonists and ICIs is only effective in tumor cells with a high expression of CD73, suggesting that CD73 may be a predictor of the efficacy of the combination therapy (Mittal et al., 2014).”
Background
A2aR antagonists: Next generation checkpoint blockade for cancer immunotherapy
Leone, R. D., Lo, Y.-C., & Powell, J. D. (2015) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2015.03.008 · Cited by 224 · see citing works
Lactate dehydrogenase: a marker of diminished antitumor immunity
Wilpe, S. V., Koornstra, R. H. T., den Brok, M. H., de Groot, J. W., Blank, C. U., de Vries, I. J. M., Gerritsen, W. R., & Mehra, N. (2020) · OncoImmunology · doi:10.1080/2162402x.2020.1731942 · Cited by 215 · see citing works
The First-in-Class Anti-CD47 Antibody Magrolimab (5F9) in Combination with Azacitidine Is Effective in MDS and AML Patients: Ongoing Phase 1b Results
Sallman, D. A., Asch, A. S., Malki, M. M. A., Lee, D. J., Donnellan, W. B., Marcucci, G., Kambhampati, S., Daver, N. G., Garcia‐Manero, G., Komrokji, R. S., et al. (2019) · Blood · doi:10.1182/blood-2019-126271 · Cited by 213 · cited 1× · see citing works
“Magrolimab is an anti-CD47 mAb that is part of an ongoing phase Ib clinical study (NCT03248479) (Sallman et al., 2019), in combination with azacitidine (DNMT inhibitor), in patients with myelodysplastic syndrome (MDS).”
Background
Vascular regulation of antitumor immunity
Munn, L. L., & Jain, R. K. (2019) · Science · doi:10.1126/science.aaw7875 · Cited by 198 · see citing works
Inhibition of the adenosine A2a receptor modulates expression of T cell coinhibitory receptors and improves effector function for enhanced checkpoint blockade and ACT in murine cancer models
Leone, R. D., Sun, I.-M., Oh, M. H., Sun, I., Wen, J., Englert, J. M., & Powell, J. D. (2018) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-018-2186-0 · Cited by 191 · cited 2× · see citing works
“Leone et al. found that the A2aR inhibitor CPI-444 significantly reduced the expression of PD1 and LAG3 in Treg cells and CD8(+) T effector cells in tumor-bearing mice, and enhanced the function of tumorinfiltrating CD8(+) T cells (Leone et al., 2018).”
Background
Pyruvate Kinase M2 Is Required for the Expression of the Immune Checkpoint PD-L1 in Immune Cells and Tumors
Pålsson‐McDermott, E. M., Dyck, L., Zasłona, Z., Menon, D., McGettrick, A. F., Mills, K. H. G., & O'Neill, L. A. J. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01300 · Cited by 173 · cited 2× · see citing works
“and bind to the HRE site on the PDL1 promoter to up-regulate the expression of PDL1 in macrophages, DCs, T cells, and tumor cells (Palsson-McDermott et al., 2017) (Fig.”
Background
Blockade of Lactate Dehydrogenase-A (LDH-A) Improves Efficacy of Anti-Programmed Cell Death-1 (PD-1) Therapy in Melanoma
Daneshmandi, S., Wegiel, B., & Seth, P. (2019) · Cancers · doi:10.3390/cancers11040450 · Cited by 168 · see citing works
Targeting Hypoxia-Induced Carbonic Anhydrase IX Enhances Immune-Checkpoint Blockade Locally and Systemically
Chafe, S. C., McDonald, P. C., Saberi, S., Nemirovsky, O., Venkateswaran, G., Burugu, S., Gao, D., Delaidelli, A., Kyle, A. H., Baker, J. H. E., et al. (2019) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-18-0657 · Cited by 166 · see citing works
Intrinsic Resistance of Solid Tumors to Immune Checkpoint Blockade Therapy
Zhao, X., & Subramanian, S. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-2379 · Cited by 157 · see citing works
Adjuvant Weekly Girentuximab Following Nephrectomy for High-Risk Renal Cell Carcinoma
Chamie, K., Donin, N. M., Klöpfer, P., Bevan, P., Fall, B., Wilhelm, O. G., Störkel, S., SAID, J. W., Gambla, M., Hawkins, R. E., et al. (2016) · JAMA Oncology · doi:10.1001/jamaoncol.2016.4419 · Cited by 147 · see citing works
Engineering therapeutic bispecific antibodies using CrossMab technology
Klein, C., Schäfer, W. M., Regula, J. T., Dumontet, C., Brinkmann, U., Bacac, M., & Umaña, P. (2018) · Methods · doi:10.1016/j.ymeth.2018.11.008 · Cited by 145 · cited 1× · see citing works
“Currently, clinical trials on the efficacy of TIM3 inhibitors such as TSR-022, LY3321367, MGB453, and INCAGN02390, as a single drug or in combination with PD1 inhibitors, in malignant tumors are underway (Ahn, 2018;Harding et al., 2019;Klein et al., 2019;Murtaza et al., 2016;Waight et al., 2018).”
Background
Deletion of Lactate Dehydrogenase-A in Myeloid Cells Triggers Antitumor Immunity
Seth, P., Csizmadia, E., Hedblom, A., Vuerich, M., Xie, H., Li, M., Longhi, M. S., & Wegiel, B. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-2938 · Cited by 143 · see citing works
Tim-3, Lag-3, and TIGIT
Joller, N., & Kuchroo, V. K. (2017) · Current topics in microbiology and immunology · doi:10.1007/82_2017_62 · Cited by 138 · see citing works
Gene signatures of tumor inflammation and epithelial-to-mesenchymal transition (EMT) predict responses to immune checkpoint blockade in lung cancer with high accuracy
Thompson, J. C., Hwang, W., Davis, C. W., Deshpande, C. G., Jeffries, S., Rajpurohit, Y. R., Krishna, V., Smirnov, D. S., Verona, R. I., Lorenzi, M. V., et al. (2019) · Lung Cancer · doi:10.1016/j.lungcan.2019.10.012 · Cited by 137 · cited 1× · see citing works
“Thompson et al. (2020) found that down-regulation of E-cadherin expression negatively affected ICBs, suggesting that high expression of E-cadherinmight be amarker for screening ICB-advantaged populations.”
Background
A2A Adenosine Receptor Gene Deletion or Synthetic A2A Antagonist Liberate Tumor-Reactive CD8+ T Cells from Tumor-Induced Immunosuppression
Kjaergaard, J., Hatfield, S., Jones, G., Ohta, A., & Sitkovsky, M. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1700850 · Cited by 132 · see citing works
Adenosine limits the therapeutic effectiveness of anti-CTLA4 mAb in a mouse melanoma model.
Iannone, R., Miele, L., Maiolino, P., Pinto, A., & Morello, S. (2014) · Europe PMC (PubMed Central) · Cited by 129 · see citing works
Immunotherapy in Breast Cancer: the Emerging Role of PD-1 and PD-L1
Bertucci, F., & Gonçalvès, A. (2017) · Current Oncology Reports · doi:10.1007/s11912-017-0627-0 · Cited by 128 · see citing works
Blockade of TIM3 relieves immunosuppression through reducing regulatory T cells in head and neck cancer
Liu, J., Wu, L., Yang, L., Deng, W., Mao, L., Wu, H., Zhang, W., & Sun, Z. (2018) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-018-0713-7 · Cited by 127 · see citing works
Hypoxia Induces Mitochondrial Defect That Promotes T Cell Exhaustion in Tumor Microenvironment Through MYC-Regulated Pathways
Liu, Y.-N., Yang, J., Huang, D.-J., Ni, H.-H., Zhang, C.-X., Zhang, L., He, J., Gu, J., Chen, H.-X., Mai, H., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01906 · Cited by 125 · see citing works
PD-1/PD-L1 in Disease
Kuol, N., Stojanovska, L., Nurgali, K., & Apostolopoulos, V. (2017) · Immunotherapy · doi:10.2217/imt-2017-0120 · Cited by 123 · cited 1× · see citing works
“autoimmune diseases and transplant rejection (Kuol et al., 2018).”
The Critical Impact of HIF-1a on Gastric Cancer Biology
Kitajima, Y., & Miyazaki, K. (2013) · Cancers · doi:10.3390/cancers5010015 · Cited by 121 · see citing works
Adaptive NK Cells Resist Regulatory T-cell Suppression Driven by IL37
Sarhan, D., Hippen, K. L., Lemire, A. M., Hying, S., Luo, X., Lenvik, T. R., Curtsinger, J., Davis, Z., Zhang, B., Cooley, S., et al. (2018) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-17-0498 · Cited by 120 · cited 1× · see citing works
“, 2019), DCs, NK cells (Sarhan et al., 2018), myeloid cells (Wang et al.”
Background
Immunotherapy in Urothelial Cancer: Recent Results and Future Perspectives
Farina, M. S., Lundgren, K. T., & Joaquim Bellmunt, B. (2017) · Drugs · doi:10.1007/s40265-017-0748-7 · Cited by 118 · see citing works
LDH-A regulates the tumor microenvironment via HIF-signaling and modulates the immune response
Serganova, I. S., Cohen, I., Vemuri, K., Shindo, M., Maeda, M., Mane, M. M., Moroz, E., Khanin, R., Satagopan, J. M., Koutcher, J. A., et al. (2018) · PLoS ONE · doi:10.1371/journal.pone.0203965 · Cited by 118 · see citing works
Impact of hypoxic tumor microenvironment and tumor cell plasticity on the expression of immune checkpoints
Lequeux, A., Noman, M. Z., Xiao, M., Sauvage, D., Van Moer, K., Viry, E., Bocci, I., Hasmim, M., Bosseler, M., Berchem, G., et al. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.05.021 · Cited by 117 · cited 1× · see citing works
“macrophages, DCs, and bone marrow-derived macrophages (BMDMs) in the TME (Barsoum et al., 2014;Lequeux et al., 2019;Noman et al., 2014).”
Background
Production of Adenosine by Ectonucleotidases: A Key Factor in Tumor Immunoescape
Ghiringhelli, F., Bruchard, M., Chalmin, F., & Rébé, C. (2012) · BioMed Research International · doi:10.1155/2012/473712 · Cited by 113 · cited 12× · see citing works
“Ado-inhibiting tumor immune microenvironment regulatory drugs Ado-inhibiting tumor immune microenvironment regulatory drugs are mainly based on the CD39-CD73-A2aR pathway.”
BackgroundInfluential
Hypoxic Stress-Induced Tumor and Immune Plasticity, Suppression, and Impact on Tumor Heterogeneity
Terry, S., Buart, S., & Chouaı̈b, S. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01625 · Cited by 111 · see citing works
MiR-3662 suppresses hepatocellular carcinoma growth through inhibition of HIF-1α-mediated Warburg effect
Chen, Z., Zuo, X., Zhang, Y., Han, G., Zhang, L., Wu, J., & Wang, X. (2018) · Cell Death and Disease · doi:10.1038/s41419-018-0616-8 · Cited by 111 · cited 1× · see citing works
“This suggests that targeting the EMT pathway may enhance the blocking effect of PD1/PDL1 in patients with esophageal squamous cell carcinoma (Chen et al., 2018a), urothelial carcinoma (Mariathasan et al., 2018) and mesenchymal metastatic tumors (Noman et al., 2017), thus improving the antitumor…”
Background
Preclinical development of a novel CD47 nanobody with less toxicity and enhanced anti-cancer therapeutic potential
Ma, L., Zhu, M., Gai, J., Li, G., Chang, Q. H., Peng, Q., Cao, L., Chen, W., Zhang, S., & Wan, Y. (2020) · Journal of Nanobiotechnology · doi:10.1186/s12951-020-0571-2 · Cited by 110 · cited 1× · see citing works
“Drug development for CD47 targets is currently underway (Ma et al., 2020).”
Background
Tim-3 enhances FcεRI-proximal signaling to modulate mast cell activation
Phong, B. L., Avery, L., Sumpter, T. L., Gorman, J. V., Watkins, S. C., Colgan, J. D., & Kane, L. (2015) · The Journal of Experimental Medicine · doi:10.1084/jem.20150388 · Cited by 108 · see citing works
TIM-3 is a potential prognostic marker for patients with solid tumors: A systematic review and meta-analysis
Zhang, Y., Cai, P., Liang, T., Wang, L., & Hu, L. (2017) · Oncotarget · doi:10.18632/oncotarget.15954 · Cited by 99 · see citing works
Systemic Antitumor Immunity by PD-1/PD-L1 Inhibition Is Potentiated by Vascular-Targeted Photodynamic Therapy of Primary Tumors
O’Shaughnessy, M. J., Murray, K. S., Rosa, S. P. L., Budhu, S., Merghoub, T., Somma, A. J., Monette, S., Kim, K., Corradi, R. B., Scherz, A. J., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-0186 · Cited by 99 · cited 2× · see citing works
“improve the efficacy of antitumor physical therapy for hypoxic tumors (Antonia et al., 2018; Chen et al., 2020; O’Shaughnessy et al., 2018).”
Background
Role of Hypoxia-Mediated Autophagy in Tumor Cell Death and Survival
Zaarour, R. F., Azakir, B., Hajam, E. Y., Nawafleh, H. H., Zeinelabdin, N. A., Engelsen, A. S. T., Thiery, J., Jamora, C., & Chouaı̈b, S. (2021) · Cancers · doi:10.3390/cancers13030533 · Cited by 98 · see citing works
Immunometabolic Dysfunction of Natural Killer Cells Mediated by the Hypoxia-CD73 Axis in Solid Tumors
Chambers, A. M., & Matosevic, S. (2019) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2019.00060 · Cited by 95 · see citing works
Dual TGF‐β and PD‐1 blockade synergistically enhances MAGE‐A3‐specific CD8+ T cell response in esophageal squamous cell carcinoma
Chen, X., Wang, L., Li, P., Song, M., Qin, G., Gao, Q., Zhang, Z., Yue, D., Wang, D., Nan, S., et al. (2018) · International Journal of Cancer · doi:10.1002/ijc.31730 · Cited by 90 · see citing works
A phase Ia/Ib study of an anti-TIM-3 antibody (LY3321367) monotherapy or in combination with an anti-PD-L1 antibody (LY3300054): Interim safety, efficacy, and pharmacokinetic findings in advanced cancers.
Harding, J. J., Patnaik, A., Moreno, V., Stein, M. N., Jankowska, A. M., de Mendizábal, N. V., Liu, Z. T., Koneru, M., & Calvo, E. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.2019.37.8_suppl.12 · Cited by 86 · cited 1× · see citing works
“Currently, clinical trials on the efficacy of TIM3 inhibitors such as TSR-022, LY3321367, MGB453, and INCAGN02390, as a single drug or in combination with PD1 inhibitors, in malignant tumors are underway (Ahn, 2018;Harding et al., 2019;Klein et al., 2019;Murtaza et al., 2016;Waight et al., 2018).”
Background
Adaptation of Operational Parameters of Cold Atmospheric Plasma for in Vitro Treatment of Cancer Cells
Gjika, E., Pal‐Ghosh, S., Tang, A., Kirschner, M., Tadvalkar, G., Canady, J., Stepp, M. A., & Keidar, M. (2018) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.7b18653 · Cited by 84 · cited 1× · see citing works
“The effectiveness of CAP is also associated with active oxygen (Gjika et al., 2018).”
Background
Photodynamic Therapy and Immune Checkpoint Blockade†
Cramer, G. M., Moon, E. K., Cengel, K. A., & Busch, T. M. (2020) · Photochemistry and Photobiology · doi:10.1111/php.13300 · Cited by 84 · see citing works
CD47 is a direct target of SNAI1 and ZEB1 and its blockade activates the phagocytosis of breast cancer cells undergoing EMT
Noman, M. Z., Moer, K. V., Marani, V., Gemmill, R. M., Tranchevent, L.-C., Azuaje, F. J., Muller, A., Chouaı̈b, S., Thiery, J. P., Berchem, G., et al. (2017) · OncoImmunology · doi:10.1080/2162402x.2017.1345415 · Cited by 79 · see citing works
OX40 and LAG3 are associated with better prognosis in advanced gastric cancer patients treated with anti-programmed death-1 antibody
Ohmura, H., Yamaguchi, T., Hanamura, F., Ito, M., Makiyama, A., Uchino, K., Shimokawa, H., Tamura, S., Esaki, T., Mitsugi, K., et al. (2020) · British Journal of Cancer · doi:10.1038/s41416-020-0810-1 · Cited by 79 · cited 6× · see citing works
“An A2a antagonist (SYN115) combined with anti-PD1 mAbs can up-regulate the expression of IFN γ and granzyme B in tumorinfiltrating CD8+T cells, and enhance anti-tumor immunity against CD73(+) tumors (Beavis et al., 2015).”
BackgroundInfluential
Hypoxic Microenvironment and Metastatic Bone Disease
Hiraga, T. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19113523 · Cited by 75 · cited 1× · see citing works
“The rapid growth of tumor cells is an important cause of TME hypoxia, and is one of the characteristic features of the TME (Hiraga, 2018).”
Background
Hypoxia‐induced HIF‐1α and ZEB1 are critical for the malignant transformation of ameloblastoma via TGF‐β‐dependent EMT
Yoshimoto, S., Tanaka, F., Morita, H., Hiraki, A., & Hashimoto, S. (2019) · Cancer Medicine · doi:10.1002/cam4.2667 · Cited by 75 · cited 1× · see citing works
“In addition, hypoxia also promotes the weakening of the adhesion of epithelial-derived tumor cells to stromal cells by activating the epithelial-mesenchymal transition (EMT), which induces the invasion and migration of tumor cells (Yoshimoto et al., 2019).”
Background
Fraxinellone has anticancer activity in vivo by inhibiting programmed cell death-ligand 1 expression by reducing hypoxia-inducible factor-1α and STAT3
Xing, Y., Mi, C., Wang, Z., Zhang, Z. H., Li, M. Y., Zuo, H. X., Wang, J. Y., Jin, X., & Ma, J. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.08.004 · Cited by 74 · see citing works
Photodynamic Therapy and Its Role in Combined Modality Anticancer Treatment
Brodin, N. P., Guha, C., & Tomé, W. A. (2014) · Technology in Cancer Research & Treatment · doi:10.1177/1533034614556192 · Cited by 71 · see citing works
Targeting tumor-associated acidity in cancer immunotherapy
Lacroix, R., Rozeman, E. A., Kreutz, M. P., Renner, K., & Blank, C. U. (2018) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-018-2195-z · Cited by 71 · cited 1× · see citing works
“Diclofenac is a glycolytic inhibitor that reduces the acidification of the TME, and combined diclofenac and PD1/CTLA4 inhibitor therapy synergistically enhanced the anti-tumor immune function in a 4T1 mouse model (Lacroix et al., 2018).”
Background
Clinical application of immune checkpoints in targeted immunotherapy of prostate cancer
Jafari, S., Molavi, O., Kahroba, H., Hejazi, M. S., Maleki‐Dizaji, N., Barghi, S., Kiaie, S. H., & Jadidi‐Niaragh, F. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03459-1 · Cited by 71 · cited 1× · see citing works
“immunosuppression and affect the anti-tumor immune response (Jafari et al., 2020).”
Background
CD8+ T cells exhaustion induced by myeloid‐derived suppressor cells in myelodysplastic syndromes patients might be through TIM3/Gal‐9 pathway
Tao, J., Han, D., Gao, S., Zhang, W., Yu, H., Liu, P., Fu, R., Li, L., & Shao, Z. (2019) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.14825 · Cited by 66 · cited 1× · see citing works
“TIM3 has four types of ligands, including carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), high-mobility group box 1 (HMGB1), phosphatidylserine (PtdSer), and Galectin-9 (Gal-9) (Tao et al., 2020).”
Background
TIM-3 expression in breast cancer
Burugu, S., Gao, D., Leung, S. C. Y., Chia, S., & Nielsen, T. O. (2018) · OncoImmunology · doi:10.1080/2162402x.2018.1502128 · Cited by 64 · cited 1× · see citing works
“Common immune checkpoints include CTLA4, PD1, PDL1, LAG3, and TIM3, which negatively regulate the immune response at different developmental stages of various tumor types (Andrews et al., 2017; Bertucci & Goncalves, 2017; Burugu et al., 2018; Joller & Kuchroo, 2017; Zhao & Subramanian, 2017).”
Background
Tumor hypoxia and reoxygenation: the yin and yang for radiotherapy
Hong, B.-J., Kim, J., Jeong, H., Bok, S., Kim, Y.-E., & Ahn, G. (2016) · Radiation Oncology Journal · doi:10.3857/roj.2016.02012 · Cited by 63 · see citing works
Association of PD-L1 and HIF-1α Coexpression with Poor Prognosis in Hepatocellular Carcinoma
Dai, X., Pi, G., Yang, S., Chen, G. Y., Liu, L., & Dong, H. (2018) · Translational Oncology · doi:10.1016/j.tranon.2018.02.014 · Cited by 63 · cited 1× · see citing works
“In conclusion, HIF-1α inhibitors have a synergistic effect with PDL1 inhibitors, and the combined application of these inhibitors may improve their individual antitumor therapeutic effect (Dai et al., 2018).”
Background
Rationale for Combining Radiotherapy and Immune Checkpoint Inhibition for Patients With Hypoxic Tumors
Eckert, F., Zwirner, K., Boeke, S., Thorwarth, D., Zips, D., & Huber, S. M. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00407 · Cited by 60 · see citing works
XIST and TSIX: Novel Cancer Immune Biomarkers in PD-L1-Overexpressing Breast Cancer Patients
Salama, E. A., Adbeltawab, R. E., & Tayebi, H. M. E. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2019.01459 · Cited by 60 · see citing works
Hypoxia-Induced Snail Expression Through Transcriptional Regulation by HIF-1α in Pancreatic Cancer Cells
Zhu, G., Huang, C., Feng, Z.-Z., Lv, X.-H., & Qiu, Z. (2013) · Digestive Diseases and Sciences · doi:10.1007/s10620-013-2841-4 · Cited by 56 · cited 1× · see citing works
“HIF-1 can combine the HRE in the proximal promoters of ZEB1, SNAIL, and TWIST, increase the expression of ZEB1, SNAIL, and TWIST, and thus down-regulate the expression of E-cadherin in tumor cells, leading to EMT (Yang et al., 2008; Zhang et al., 2015; Zhu et al., 2013; Zhu et al., 2018).”
Background
Metformin enhances gefitinib efficacy by interfering with interactions between tumor-associated macrophages and head and neck squamous cell carcinoma cells
Yin, X., Han, S., Song, C., Zou, H., Wei, Z., Xu, W., Ran, J., Tang, C., Wang, Y., Cai, Y., et al. (2019) · Cellular Oncology · doi:10.1007/s13402-019-00446-y · Cited by 55 · see citing works
Carbonic anhydrase 9 (CA9) expression in non-small-cell lung cancer: correlation with regulatory FOXP3+T-cell tumour stroma infiltration
Giatromanolaki, A. N., Harris, A. L., Banham, A. H., Contrafouris, C., & Koukourakis, M. I. (2020) · British Journal of Cancer · doi:10.1038/s41416-020-0756-3 · Cited by 51 · see citing works
Overexpression of HIF1α and CAXI predicts poor outcome in early-stage triple negative breast cancer
Jin, M., Lee, H., Park, I. A., Chung, Y. R., Im, S., Lee, K.-H., Moon, H., Han, W., Kim, K., Kim, T., et al. (2016) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s00428-016-1953-6 · Cited by 47 · see citing works
Inhibition of HIF-1α by PX-478 suppresses tumor growth of esophageal squamous cell cancer in vitro and in vivo.
(2017) · Europe PMC (PubMed Central) · Cited by 44 · see citing works
Efficacy and Tolerability of Tremelimumab in Locally Advanced or Metastatic Urothelial Carcinoma Patients Who Have Failed First-Line Platinum-Based Chemotherapy
Sharma, P., Sohn, J., Shin, S. J., Oh, D., Keam, B., Lee, H. J., Gizzi, M., Kalinka‐Warzocha, E., Vos, F. D., Ruscica, D., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-1635 · Cited by 43 · see citing works
Something in the Air: Hyperoxic Conditioning of the Tumor Microenvironment for Enhanced Immunotherapy
Leone, R. D., Horton, M. R., & Powell, J. D. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.03.014 · Cited by 42 · see citing works
CTLA4 has a profound impact on the landscape of tumor-infiltrating lymphocytes with a high prognosis value in clear cell renal cell carcinoma (ccRCC)
Liu, S., Wang, F., Tan, W., Zhang, L., Dai, F., Wang, Y., Fan, Y., Yuan, M., Yang, D., Zheng, Y., et al. (2020) · Cancer Cell International · doi:10.1186/s12935-020-01603-2 · Cited by 36 · cited 3× · see citing works
“Previous studies have shown that tumor hypoxia can lead to the exhaustion of T cells and natural killer (NK) cells (Chambers & Matosevic, 2019; Liu et al., 2020b).”
Background
Discovery of TSR-022, a novel, potent anti-human TIM-3 therapeutic antibody
Murtaza, A., Laken, H., Correia, J. D. S., McNeeley, P. A., Altobell, L. J., Zhang, J., Vancutsem, P. M., Wilcoxen, K., & Jenkins, D. (2016) · European Journal of Cancer · doi:10.1016/s0959-8049(16)32903-3 · Cited by 34 · cited 1× · see citing works
“Currently, clinical trials on the efficacy of TIM3 inhibitors such as TSR-022, LY3321367, MGB453, and INCAGN02390, as a single drug or in combination with PD1 inhibitors, in malignant tumors are underway (Ahn, 2018;Harding et al., 2019;Klein et al., 2019;Murtaza et al., 2016;Waight et al., 2018).”
Background
Superior Efficacy of Tumor Cell Vaccines Grown in Physiologic Oxygen
Olin, M. R., Andersen, B. M., Zellmer, D. M., Grogan, P. T., Popescu, F. E., Xiong, Z., Forster, C. L., Seiler, C., SantaCruz, K. S., Chen, W., et al. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-1572 · Cited by 31 · see citing works
SENP1-mediated deSUMOylation of USP28 regulated HIF-1α accumulation and activation during hypoxia response
Du, S.-C., Zhu, L., Wang, Y.-X., Liu, J., Zhang, D., Chen, Y.-L., Peng, Q., Liu, W., & Liu, B. (2019) · Cancer Cell International · doi:10.1186/s12935-018-0722-9 · Cited by 31 · cited 1× · see citing works
“The activation of HIF-1α promotes tumor angiogenesis (Du et al., 2019), promotes distant metastasis of”
Background
ARC-8: Phase I/Ib study to evaluate safety and tolerability of AB680 + chemotherapy + zimberelimab (AB122) in patients with treatment-naive metastatic pancreatic adenocarcinoma (mPDAC).
Manji, G. A., Wainberg, Z. A., Krishnan, K., Giafis, N., Udyavar, A. R., Quah, C. S., Scott, J., Berry, W., DiRenzo, D. M., Gerrick, K. Y., et al. (2021) · Journal of Clinical Oncology · doi:10.1200/jco.2021.39.3_suppl.404 · Cited by 28 · see citing works
Reciprocal loop of hypoxia‐inducible factor‐1α (HIF‐1α) and metastasis‐associated protein 2 (MTA2) contributes to the progression of pancreatic carcinoma by suppressing E‐cadherin transcription
Zhu, S., Deng, S.-J., He, C., Liu, M., Chen, H., Zeng, Z., Zhong, J., Zeng, Y., Deng, S., Wu, H., et al. (2018) · The Journal of Pathology · doi:10.1002/path.5089 · Cited by 27 · cited 1× · see citing works
“HIF-1 can combine the HRE in the proximal promoters of ZEB1, SNAIL, and TWIST, increase the expression of ZEB1, SNAIL, and TWIST, and thus down-regulate the expression of E-cadherin in tumor cells, leading to EMT (Yang et al., 2008; Zhang et al., 2015; Zhu et al., 2013; Zhu et al., 2018).”
Background
Abstract CT026: Evidence of immune activation in the first-in-human Phase Ia dose escalation study of the adenosine 2a receptor antagonist, AZD4635, in patients with advanced solid tumors
Bendell, J. C., Bauer, T. M., Patel, M. R., Falchook, G. S., Karlix, J. L., Lim, E. A., Mugundu, G. M., Mitchell, P., Pouliot, G. P., Moorthy, G., et al. (2019) · Cancer Research · doi:10.1158/1538-7445.am2019-ct026 · Cited by 26 · cited 3× · see citing works
“The phase I clinical trial of the A2aR antagonist AZD4635 (NCT02740985) (Bendell et al., 2019) showed that, of the eight patients with metastatic castration-resistant prostate cancer (mCRPC) with evaluable tumor lesions, one patient who received AZD4635 monotherapy achieved a partial response (PR), while one patient w…”
BackgroundInfluential
Suppression of the expression of hypoxia-inducible factor-1α by RNA interference alleviates hypoxia-induced pulmonary hypertension in adult rats
Li, Y., Shi, B., Huang, L., Wang, X., Yu, X., Guo, B., & Ren, W. (2016) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2016.2773 · Cited by 25 · cited 1× · see citing works
“constitutively expressed protein, the HIF-1β subunit (Li et al., 2016).”
Possible therapeutic applicability of galectin-9 in cutaneous T-cell lymphoma
Nakajima, R., Miyagaki, T., Kamijo, H., Oka, T., Shishido-Takahashi, N., Suga, H., Sugaya, M., & Sato, S. (2019) · Journal of Dermatological Science · doi:10.1016/j.jdermsci.2019.09.004 · Cited by 23 · cited 1× · see citing works
“increased in TIM3-overexpressing EL4 mice (Nakajima et al., 2019).”
Abstract 3825: INCAGN02390, a novel antagonist antibody that targets the co-inhibitory receptor TIM-3
Waight, J. D., Iyer, P., Breous-Nystrom, E., Riordan, C., Findeis, M. A., Underwood, D. J., Connolly, J., Sanicola-Nadel, M., Nastri, H. G., Scherle, P., et al. (2018) · Cancer Research · doi:10.1158/1538-7445.am2018-3825 · Cited by 19 · see citing works
HIF‐1a expression and differential effects on survival in patients with oral cavity, larynx, and oropharynx squamous cell carcinomas
Swartz, J. E., Wegner, I., Noorlag, R., van Kempen, P. M. W., van Es, R. J. J., de Bree, R., & Willems, S. M. (2020) · Head & Neck · doi:10.1002/hed.26530 · Cited by 19 · see citing works
Oxygen Is a Master Regulator of the Immunogenicity of Primary Human Glioma Cells
Olin, M. R., Andersen, B. M., Litterman, A. J., Grogan, P. T., Sarver, A. L., Robertson, P. T., Liang, X., Chen, W., Parney, I. F., Hunt, M. A., et al. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-1166 · Cited by 18 · see citing works
Requirement of NK Cells for Selective A 2A Receptor Blockade to Suppress CD73 + Tumor Metastasis
Qin, L., Thompson, L. F., Kuzel, T. M., & Zhang, B. (2013) · Immunotherapy · doi:10.2217/imt.13.154 · Cited by 14 · cited 1× · see citing works
“In addition to A2aR, blocking CD73 can also prevent tumor growth and metastasis (Qin et al., 2014).”
Background
Elevated TIM3 expression of T helper cells affects immune system in patients with myelodysplastic syndrome
Fu, R., Li, L., Hu, J., Wang, Y., Tao, J., Liu, H., Liu, Z., & Zhang, W. (2019) · Journal of Investigative Medicine · doi:10.1136/jim-2019-001059 · Cited by 12 · cited 1× · see citing works
“, 2020), Treg cells (Fu et al., 2019), DCs, NK cells (Sarhan et al.”
Background
Fecal bacteria from ulcerative colitis patients downregulate Tim-3-mediated inhibitory effects on monocytes in vitro
Wang, S., Liu, Y., Yuan, X., Yao, L., Yang, S., & Ma, R. (2018) · Microbial Pathogenesis · doi:10.1016/j.micpath.2018.12.043 · Cited by 10 · see citing works
MS28.02 Combination IO+IO
Ahn, M.-J. (2018) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2018.08.194 · Cited by 8 · cited 1× · see citing works
“Currently, clinical trials on the efficacy of TIM3 inhibitors such as TSR-022, LY3321367, MGB453, and INCAGN02390, as a single drug or in combination with PD1 inhibitors, in malignant tumors are underway (Ahn, 2018;Harding et al., 2019;Klein et al., 2019;Murtaza et al., 2016;Waight et al., 2018).”
Background

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Immune Checkpoint Inhibitors in Cancer Therapy
Shiravand, Y., Khodadadi, F., Kashani, S. M. A., Hosseini-Fard, S. R., Hosseini, S., Sadeghirad, H., Ladwa, R., O’Byrne, K., & Kulasinghe, A. (2022) · Current Oncology · doi:10.3390/curroncol29050247 · Cited by 1,353 · see citing works
“has been shown to modulate the expression of immune checkpoints such as CTLA-4, CD47, PD-1/L-1, and TIM3 in order to manipulate immune cells’ mediated anti-tumour response, thereby inhibiting immune surveillance [126].”
Background
Photodynamic therapy combined with immunotherapy: Recent advances and future research directions
Warszyńska, M., Repetowski, P., & Dąbrowski, J. M. (2023) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2023.215350 · Cited by 138 · see citing works
Tumour response to hypoxia: understanding the hypoxic tumour microenvironment to improve treatment outcome in solid tumours
Bigos, K. J. A., Quiles, C. G., Lunj, S., Smith, D. J., Krause, M., Troost, E. G. C., West, C., Hoskin, P., & Choudhury, A. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1331355 · Cited by 142 · see citing works
The impact of hypoxia on immune state in cancer
Mortezaee, K., & Majidpoor, J. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.120057 · Cited by 100 · see citing works
Immunotherapy in glioblastoma treatment: Current state and future prospects
Pinheiro, S. L. R., Lemos, F. F. B., Marques, H. S., Luz, M. S., Silva, L. G. D. O., dos Santos, C. F. S. M., Evangelista, K. D. C., Calmon, M. S., Loureiro, M. S., & de Melo, F. F. (2023) · World Journal of Clinical Oncology · doi:10.5306/wjco.v14.i4.138 · Cited by 92 · see citing works
Targeting HIF-2α in the Tumor Microenvironment: Redefining the Role of HIF-2α for Solid Cancer Therapy
Davis, L., Recktenwald, M., Hutt, E., Fuller, S., Briggs, M., Goel, A., & Daringer, N. (2022) · Cancers · doi:10.3390/cancers14051259 · Cited by 83 · see citing works
Immunotherapy in soft tissue and bone sarcoma: unraveling the barriers to effectiveness
Panagi, M., Pilavaki, P., Constantinidou, A., & Stylianopoulos, T. (2022) · Theranostics · doi:10.7150/thno.72800 · Cited by 55 · see citing works
“Hypoxia may also upregulate PD-1, CTLA-4 and TGF-β expression on the surface of T cells through the adenosine (Ado-A2aR) pathway which further promotes immune tolerance by diverting the cytokine and cellular profile of the TME away from cytotoxic T cell inflammation, leading to tumor progression and metastasis [125].”
Background
Hypoxia as a potential inducer of immune tolerance, tumor plasticity and a driver of tumor mutational burden: Impact on cancer immunotherapy
Khouzam, R. A., Janji, B., Thiery, J., Zaarour, R. F., Chamseddine, A. N., Mayr, H., Savagner, P., Kiéda, C., Gad, S., Buart, S., et al. (2023) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2023.11.008 · Cited by 51 · see citing works
Combination of PD-1/PD-L1 and CTLA-4 inhibitors in the treatment of cancer – a brief update
Park, J., & Skålhegg, B. S. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1680838 · Cited by 60 · see citing works
Immunotherapeutic Strategies for the Treatment of Glioblastoma: Current Challenges and Future Perspectives
Salvato, I., & Marchini, A. (2024) · Cancers · doi:10.3390/cancers16071276 · Cited by 50 · see citing works
The role of immune checkpoints in antitumor response: a potential antitumor immunotherapy
Mejía-Guarnizo, L. V., Monroy-Camacho, P. S., Turizo-Smith, A. D., & Rodríguez-García, J. A. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1298571 · Cited by 48 · see citing works
“Although CD28 and CTLA-4 share the same ligands, they have opposite functions: CTLA-4 inhibits T cell activation while CD-28 activates it (5) and differ in expression, cellular localization, and lymphocyte traf ﬁ cking (16, 17).”
BackgroundInfluential
Physicochemical aspects of the tumour microenvironment as drivers of vasculogenic mimicry
Andreucci, E., Peppicelli, S., Ruzzolini, J., Bianchini, F., & Calorini, L. (2022) · Cancer and Metastasis Reviews · doi:10.1007/s10555-022-10067-x · Cited by 43 · see citing works
“Indeed, upon exposure to acidosis or hypoxia, tumour cells release a large variety of immunosuppressive molecules, such as IL10, TGFβ and VEGF, that act on the immune system in three main ways: inhibiting immune cell proliferation and survival [106, 107], affecting immune cell function [106, 108] and regulating the si…”
Background
Lighting up the fire in the microenvironment of cold tumors: a major challenge to improve cancer immunotherapy
Benoit, A., Vogin, G., Duhem, C., Berchem, G., & Janji, B. (2023) · Cells · doi:10.3390/cells12131787 · Cited by 39 · see citing works
“Finally, hypoxia triggers the activation of autophagy, thus impairing tumor cell susceptibility to NK and CTL-mediated killing [134].”
Background
Barriers to Immunotherapy in Ovarian Cancer: Metabolic, Genomic, and Immune Perturbations in the Tumour Microenvironment
Johnson, R. L., Cummings, M., Thangavelu, A., Theophilou, G., Jong, D. D., & Orsi, N. M. (2021) · Cancers · doi:10.3390/cancers13246231 · Cited by 39 · see citing works
Construction of a hypoxia-immune-related prognostic panel based on integrated single-cell and bulk RNA sequencing analyses in gastric cancer
Deng, C., Deng, G., Chu, H., Chen, S., Chen, X., Li, X., He, Y., Sun, C., & Zhang, C. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1140328 · Cited by 34 · see citing works
“Hypoxia significantly upregulates PD-L1 expression in immune cells in a HIF-1a-dependent manner (36).”
Result
Immunotherapy in the Battle Against Bone Metastases: Mechanisms and Emerging Treatments
Hamza, F. N., & Mohammad, K. S. (2024) · Pharmaceuticals · doi:10.3390/ph17121591 · Cited by 25 · see citing works
Society for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors with targeted therapies
Atkins, M. B., Ascierto, P. A., Feltquate, D., Gulley, J. L., Johnson, D. B., Khushalani, N. I., Sosman, J. A., Yap, T. A., Kluger, H. M., Sullivan, R. J., et al. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-005923 · Cited by 24 · see citing works
The future of immunotherapy for diffuse large B‐cell lymphoma
Duell, J., & Westin, J. R. (2024) · International Journal of Cancer · doi:10.1002/ijc.35156 · Cited by 22 · see citing works
“73,74 In DLBCL, overexpression of CD47 was associated with worse clinical outcomes in patients with DLBCL treated with CHOP±R. 75”
Influential
Immune checkpoints between epithelial-mesenchymal transition and autophagy: A conflicting triangle
Cordani, M., Strippoli, R., Trionfetti, F., Behrooz, A. B., Rumio, C., Velasco, G., Ghavami, S., & Marcucci, F. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.216661 · Cited by 20 · see citing works
Self-oxygenated co-assembled biomimetic nanoplatform for enhanced photodynamic therapy in hypoxic tumor
Zhang, B., Lin, L., Mao, J., Mo, W., Li, Z., Wang, S., Tang, Y., Cui, C., Wu, Y., & Yu, Z. (2023) · Chinese Chemical Letters · doi:10.1016/j.cclet.2023.108518 · Cited by 20 · see citing works
Non-immune cell components in tumor microenvironment influencing lung cancer Immunotherapy
Zhang, J., Liu, S., Chen, X., Xu, X., & Xu, F. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115336 · Cited by 20 · see citing works
Glioblastoma and Immune Checkpoint Inhibitors: A Glance at Available Treatment Options and Future Directions
Rodriguez, S. M. B., Tătăranu, L. G., Kamel, A., Turliuc, Ș., Rizea, R. E., & Dricu, A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms251910765 · Cited by 20 · see citing works
“HIF1-α is responsible for the upregulation of immunomodulatory surface ligands like cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death ligand 1 (PD-L1), causing the inhibition of the anti-tumor immune responses [89].”
Background
Improving tumor microenvironment assessment in chip systems through next-generation technology integration
Gaebler, D., Hachey, S. J., & Hughes, C. C. W. (2024) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2024.1462293 · Cited by 19 · see citing works
“Hypoxia and acidosis, resulting from abnormal tumor vasculature, attract immunosuppressive cells, diminish effector T cell activity, and further impede therapeutic delivery and ef ﬁ cacy (Hu et al., 2021; Khouzam et al., 2022; Mortezaee et al., 2023).”
Background
Enhancement of immune surveillance in breast cancer by targeting hypoxic tumor endothelium: Can it be an immunological switch point?
Thomas, J. A., Moly, A. G. G., Xavier, H., Suboj, P., Ladha, A., Gupta, G., Singh, S. K., Palit, P., & Babykutty, S. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1063051 · Cited by 17 · see citing works
Boosting immune responses in lung tumor immune microenvironment: A comprehensive review of strategies and adjuvants
Gao, F., You, X., Yang, L., Zou, X., & Sui, B. (2024) · International Reviews of Immunology · doi:10.1080/08830185.2024.2333275 · Cited by 14 · see citing works
“First, hypoxia can induce the expression of PD-1 and CTLA-4 in CTLs [252].”
Associations between HIFs and tumor immune checkpoints: mechanism and therapy
Liu, J., Jiang, Y., Chen, L., Qian, Z., & Zhang, Y. (2024) · Discover Oncology · doi:10.1007/s12672-023-00836-7 · Cited by 13 · see citing works
“It has been demonstrated that hypoxia alters the levels of immune checkpoints like CTLA-4, PD-1/L-1, CD47, and TIM3 to modify the immune cell-induced anti-tumor response, thus suppressing immune surveillance [64].”
Background
Immune Resistance in Glioblastoma: Understanding the Barriers to ICI and CAR-T Cell Therapy
Eckert, T., Zobaer, M. S., Boulos, J., Alexander-Bryant, A. A., Baker, T. G., Rivers, C., Das, A., Vandergrift, W. A., Santos, J. L. M., Zukas, A. M., et al. (2025) · Cancers · doi:10.3390/cancers17030462 · Cited by 10 · see citing works
“This, in turn, reduces the acti-Cancers vation of surrounding cytotoxic T lymphocytes and weakens the anti-tumor response [29]. response [29].”
Influential
CD47-mediated tumor microenvironment remodeling: a central mechanism in immune evasion
Yuan, H., Zhu, L., Yang, L., Yi, Y., & Lv, T. (2025) · Acta Biochimica et Biophysica Sinica · doi:10.3724/abbs.2025071 · Cited by 8 · see citing works
“PD1, PDL1, lymphocyte activation gene 3 (LAG3), T - cell immu - noglobulin domain and mucin domain - 3 (TIM3), and inhibit T - cell activation through various mechanisms, thereby suppressing the body’s antitumor immune response and leading to tumor immune escape [127].”
Hydrogen sulfide at the intersection of hypoxia and oxidative stress: implications for lung cancer progression and treatment – a narrative review
Obeagu, E. I., & Aban, J. L. (2026) · Annals of Medicine and Surgery · doi:10.1097/ms9.0000000000004731 · Cited by 6 · see citing works
“Targeting hypoxia – whether through normalization of tumor vasculature, inhibition of HIF signaling, or modulation of downstream pathways – remains a key strategy under investigation (Table 1) [ 21 ] .”
Hypoxia-related tumor environment correlated with immune infiltration and therapeutic sensitivity in diffuse large B-cell lymphoma
Liu, C., & Liu, L. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.1037716 · Cited by 6 · see citing works
“In the hypoxic tumor microenvironment, hypoxia-inducible factor 1 (HIF-1) and its pathway play roles in suppressing the innate and adaptive immune systems to evade immune attack by inducing the expression of immunosuppressive factors and immune checkpoint molecules (Hu et al., 2021; You et al., 2021).”
Background
Adenosine receptors in breast cancer
Mahdizadeh, M., Heydari, N., Shafiei, A., Akbari, H., & Jafari, S. M. (2024) · Molecular Biology Reports · doi:10.1007/s11033-024-09382-z · Cited by 5 · see citing works
“The TME is a complicated and dynamic part that describes the non-cancerous cells of the tumor environment, and it plays a role in the development of tumor cells [57, 58].”
Immune checkpoint inhibitor (ICI) therapy in central nervous system cancers: State-of-the-art and future outlook
Sadegh, R. K., Saleki, K., & Rezaei, N. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.114837 · Cited by 5 · see citing works
Targeting autophagy in dysfunctional tumor vasculature
Lin, Q., Cai, B., Ke, R., Ni, X., Wan, X., Chen, L., Huang, T., Shan, X., & Wang, B. (2025) · iScience · doi:10.1016/j.isci.2025.114084 · Cited by 5 · see citing works
“246 VEGF-A signaling impairs immune responses by stimulating inhibitory receptors (e.g., Tim3, PD1, and CTLA-4) on intratumoral T cells.”
The hypoxic tumor microenvironment: Functional and metabolic reprogramming of key immune populations
Ojaroodi, A. F., Shokravi, S., Eskandarzadeh, S., Ghahremanzadeh, A., Alizadeh, F., Amirikar, F., Mobayen, G., Mahrooghi, D., Lahouty, M., Shamsasenjan, K., et al. (2026) · Pathology - Research and Practice · doi:10.1016/j.prp.2026.156443 · Cited by 3 · see citing works
Heterogeneity, Measurement, and Clinical Implications of Oxygenation, Cell Signaling, and Redox Biology in Glioblastoma and Adult Diffuse Gliomas, with Context from Other Brain Tumors
Das, A., Bailes, J. E., Barlow, A., & Aksenov, D. P. (2026) · Antioxidants · doi:10.3390/antiox15040505 · Cited by 3 · see citing works
Role of Fibrinogen-like Protein 1 in Tumor Recurrence Following Hepatectomy
Shafieizadeh, Z., Shafieizadeh, Z., Davoudi, M., Afrisham, R., & Miao, X. (2024) · Journal of Clinical and Translational Hepatology · doi:10.14218/jcth.2023.00397 · Cited by 3 · see citing works
“81 85 As mentioned above, FGL1 is the primary ligand of the LAG-3 receptor.”
Background
A DNA Replication Stress-Based Prognostic Model for Lung Adenocarcinoma
Shi, S., Wen, G., Lei, C., Chang, J., Yin, X., Liu, X., & Huang, S. (2023) · Acta Naturae · doi:10.32607/actanaturae.25112 · Cited by 2 · see citing works
Comprehensive genome editing confers ‘off-the-shelf’ CAR-T cells superior efficacy against solid tumorsPreprint
Murray, R. C., Navarrete, N. R. R., Desai, K., Chowdhury, M. R., Chilakapati, S. R., Chong, B., Messana, A., Sobon, H., Rocha, J., Musenge, F. M., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.08.03.551705 · Cited by 2 · see citing works
“To determine whether multiplex gene editing confers functional resistance to these biochemical and immunological inhibitory pathways, TKO CAR-T cells were tumor stimulated in an in vitro system that concomitantly recapitulates Ado, PD-L1 and TGF-β inhibition.”
BackgroundInfluential
TACE, lenvatinib, and PD-1 inhibitors in unresectable advanced hepatocellular carcinoma: an exploratory retrospective cohort study
Zhao, H., Li, T., Zhang, Y. B., Song, Y., & Li, M. (2026) · BMC Gastroenterology · doi:10.1186/s12876-026-04985-1 · Cited by 1 · see citing works
“However, the ensuing hypoxic microenvironment often upregulates immunosuppressive factors such as VEGF, PD-L1, and hypoxia-inducible factor-1α (HIF-1α), thereby counteracting T-cell activation [24, 27, 28].”
N-myristoyltransferase-mediated protein myristoylation: molecular mechanisms, pathological roles, and targeted therapeutic strategies
Liu, W., Chen, Z., Huang, Z., & Chen, L. (2026) · Journal of Advanced Research · doi:10.1016/j.jare.2026.06.010 · Cited by 1 · see citing works
Immune checkpoints and immunoregulation in metabolic diseases and cancers: pathological mechanisms and therapeutic potential
Xiang, M., Liu, S., Xiao, D., & Tao, Y. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-026-02810-5 · Cited by 1 · see citing works
“190 Therefore, CTLA-4 blockade would more effectively reverse this exaggerated suppression.”
Author Index
Authors, V. (2013) · Current Oncology · doi:10.3747/co.20.1906
Tarloxotinib targets tumor hypoxia to improve therapeutic efficacy of immune checkpoint inhibition in a TLR9 dependent mannerPreprint
Fu, Z., Jackson-Patel, V., Farrand, K. J., Guise, C. P., Silva, S., Dabb, A. R., Lin, X., Liu, E., Ashoorzadeh, A., Smaill, J. B., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.02.24.635378
“The function of effector T cells and dendritic cells (DC) is compromised through adenosine accumulation (12), while hypoxia-inducible factor (HIF)-1 expression leads to upregulation of inhibitory molecules such as CTLA-4 and PD-L1 (13, 14).”
The Interaction between the Bone Marrow Microenvironment and Immunotherapy in Multiple Myeloma: Mechanisms, Challenges, and Prospects
张, 慧. (2025) · Advances in Clinical Medicine · doi:10.12677/acm.2025.1541037
Role of the tumor microenvironment in promoting treatment resistance in urothelial carcinoma (Review)
Li, Y., Su, P., & Sun, X. (2025) · Molecular Medicine Reports · doi:10.3892/mmr.2025.13658 · Cited by 1 · see citing works
“Studies have revealed that the presence of hypoxic regions within tumors can activate hypoxia‑inducible factors, leading to increased expression of genes associated with aggressive behavior and treatment resistance (10,14).”
Exploring the role of metabolic disorders and gut microbiome in immune checkpoint regulation in cancer: PI3K/AKT/mTOR focus
Abedi, A., Moghaddam, M. M., Kachuei, R., & Fooladi, A. A. I. (2026) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-026-01171-5
Advances in Immunotherapies for Targeting Cancer Stem Cells in a Tumor Microenvironment: Emerging Strategies and Clinical Prospects
Oh, N., & Trinh, V. N. (2026) · Cells · doi:10.3390/cells15100910
“In addition to previously described canonical immune evasion mechanisms, hypoxia further exacerbates immune suppression by HIF-mediated regulation, including upregulation of immune checkpoint ligands, recruitment of suppressive immune cell populations, and inhibition of DCs maturation [254–256].”
Hypoxia‐Associated Molecular Subtypes Reveal Immune Checkpoint, Ferroptosis, and m6A Regulatory Heterogeneity in Pediatric Vasculitis
Liu, B. (2026) · Human Mutation · doi:10.1155/humu/7451086
“Persistent antigenic stimulation, endothelial injury, inflammatory cytokines, and HIF-dependent transcriptional programs can induce inhibitory checkpoint molecules such as PDCD1/PD-1, TIM-3, and LAG3 in T cells, myeloid cells, and endothelial-interacting immune populations [28–30].”
Breaking tumor barriers: Nanoscale strategies for remodeling the extracellular matrix to enhance cancer therapy
Zhou, D., Wang, D., Zhang, S., Li, M., Liu, H., Li, M., & Chen, Y. (2026) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2026.108939
Mechanisms of resistance to immune checkpoint inhibitors in renal cell carcinoma and novel treatment strategies
Chen, L., Cheng, J., & Mao, S. (2026) · Frontiers in Oncology · doi:10.3389/fonc.2026.1984645
“Meanwhile, hypoxia facilitates adenosine accumulation in the TME, strongly inhibiting T-cells and NK-cells activity through A2A receptor (43).”
Tarloxotinib targets tumor hypoxia to improve therapeutic efficacy of immune checkpoint inhibition in a MyD88-dependent manner
Fu, Z., Jackson-Patel, V., Farrand, K. J., Guise, C. P., Silva, S., Dabb, A., Lin, X., Liu, E., Ashoorzadeh, A., Smaill, J. B., et al. (2026) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2025-013057

Hypoxia and programmed cell death-ligand 1 expression in the tumor microenvironment: a review of the effects of hypoxia-induced factor-1 on immunotherapy
Chamani, F. K., Etebari, A., Hajivalili, M., Mosaffa, N., & Jalali, S. A. (2024) · Molecular Biology Reports · doi:10.1007/s11033-023-08947-8 · Cited by 6 · see citing works
The impact of hypoxia on immune state in cancer
Mortezaee, K., & Majidpoor, J. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.120057 · Cited by 100 · see citing works
Strategies to Target Hypoxia-Induced Immune Suppression and Immune Escape Mechanisms
Kamplikar, P., Mukherjee, S., & Kanwar Jagat, R. (2026) · CRC Press eBooks · doi:10.1201/9781003477419-4
[Immunomodulation in the tumor microenvironment: Therapeutic potential of combined inhibition of tumor hypoxia and PD-1/ PD-L1].
Svajda, L., Cserepes, M., Hegyi, B., Niczky, T., & Tóvári, J. (2024) · PubMed Central · Cited by 2 · see citing works
Targeting hypoxia in the tumor microenvironment: a potential strategy to improve cancer immunotherapy
Wang, B., Zhao, Q., Zhang, Y., Liu, Z., Zheng, Z., Liu, S., Meng, L., Xin, Y., & Jiang, X. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-020-01820-7 · Cited by 315 · see citing works

Authors: Hu, M., Li, Y., Lu, Y., Wang, M., Li, Y., Wang, C., Li, Q., & Zhao, H.
Affiliations: Shanxi Medical University (CN)
Capital Medical University (CN)
Hainan Medical University (CN)
Corresponding author: Li, Qin
Zhao, Hong
ORCID: Hu, Min
Li, Yongfu
Lu, Yuting
Wang, Miao
Li, Yingrui
Wang, Chaoying
Li, Qin
Zhao, Hong
Venue: PeerJ
Publisher: PeerJ
Published: 2021-05-07
Volume: 9
Pages: e11306
ISSN: 2167-8359 (ISSN-L)
DOI: 10.7717/peerj.11306
PMC: PMC8109006
OpenAlex: W3161646106
Cited by: 51
References: 133
Citations by year: 2026: 12 · 2025: 8 · 2024: 11 · 2023: 12 · 2022: 5 · 2021: 2 · 2013: 1
FWCI: 2.73
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
Locations: PeerJ (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
Keywords: tumor hypoxia, tumor microenvironment, immune checkpoint, immune checkpoint inhibitors, HIF-1α, adenosine A2A receptor, glycolysis, epithelial-mesenchymal transition, CTLA-4, PD-1/PD-L1, CD47, LAG-3, TIM-3, tumor immune evasion, immunotherapy resistance, combination therapy, predictive biomarkers, lung cancer, urothelial carcinoma, gynecological tumors

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The regulation of immune checkpoints by the hypoxic tumor microenvironment

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