Challenges and beyond: Targeting hypoxia-inducible factors for anti-tumor immunity restoration
Hypoxia-inducible factors (HIFs) are key regulators linked to hypoxia, metabolism, and tumor immunity. Current studies on HIF-targeted cancer immunotherapy primarily focus on single cell types or pathways and often lack subunit selectivity, making therapeutic outcomes difficult to predict. In this article, we review how HIF-1α and HIF-2α shape the immunosuppressive tumor microenvironment across metabolism, vasculature, and immune cell programs. We explore the advantages and challenges of current strategies, including HIF inhibition combined with immune checkpoint blockade, adoptive cell therapy, regulatory T cell or myeloid modulation, and vascular normalization, noting that existing evidence remains limited and fragmented. We propose that rational HIF targeting may support tumor immunity through a coordinated modulation of multiple axes rather than targeting individual pathways in isolation. Finally, we introduce two forward-looking directions: an organoid-based microfluidic tumor-on-a-chip model as a platform to systematically evaluate HIF-targeted interventions, and rhythm-aligned, intermittent HIF modulation as a potential strategy to reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy efficacy.
Aquino-Galvez, A., Gonzalez-Avila, G., Delgado-Tello, J., Castillejos-Lopez, M., Mendoza-Milla, C., Zuniga, J., Checa, M., Maldonado-Martinez, H. A., Trinidad-Lopez, A., Cisneros, J., Torres-Espindola, L. M., Hernandez-Jimenez, C., Sommer, B., Cabello-Gutierrez, C., & Gutierrez-Gonzalez, L. H. (2016). Effects of 2-methoxyestradiol on apoptosis and HIF-1α and HIF-2α expression in lung cancer cells under normoxia and hypoxia. Oncology Reports, 35(1), 577–583. https://doi.org/10.3892/or.2015.4399
Arnaiz, E., Miar, A., Bridges, E., Prasad, N., Hatch, S. B., Ebner, D., Lawrie, C. H., & Harris, A. L. (2021). Differential effects of HIF-2α antagonist and HIF-2α silencing in renal cancer and sensitivity to repurposed drugs. BMC Cancer, 21(1). https://doi.org/10.1186/s12885-021-08616-8
Bailey, C. M., Liu, Y., Liu, M., Du, X., Devenport, M., Zheng, P., Liu, Y., & Wang, Y. (2022). Targeting HIF-1α abrogates PD-L1-mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues. Journal of Clinical Investigation, 132(9). https://doi.org/10.1172/jci150846
Ball, A. T., Mohammed, S., Doigneaux, C., Gardner, R. M., Easton, J. W., Turner, S., Essex, J. W., Pairaudeau, G., & Tavassoli, A. (2024). Identification and development of cyclic peptide inhibitors of HIF-1α and 2α that disrupt hypoxia-response signaling in cancer cells. Journal of the American Chemical Society, 146(13), 8877–8886. https://doi.org/10.1021/jacs.3c10508
Bartholomaus, I., Kawakami, N., Odoardi, F., Schlager, C., Miljkovic, D., Ellwart, J. W., Klinkert, W. E., Flugel-Koch, C., Issekutz, T. B., Wekerle, H., & Flugel, A. (2009). Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature, 462(7269), 94–98. https://doi.org/10.1038/nature08478
Becker, C. M., Rohwer, N., Funakoshi, T., Cramer, T., Bernhardt, W., Birsner, A., Folkman, J., & D’Amato, R. J. (2008). 2-methoxyestradiol inhibits HIF-1α and suppresses growth of lesions in a mouse model of endometriosis. American Journal of Pathology, 172(2), 534–544. https://doi.org/10.2353/ajpath.2008.061244
Bertout, J. A., Majmundar, A. J., Gordan, J. D., Lam, J. C., Ditsworth, D., Keith, B., Brown, E. J., Nathanson, K. L., & Simon, M. C. (2009). HIF-2α inhibition promotes p53 pathway activity, tumor cell death, and radiation responses. Proceedings of the National Academy of Sciences of the United States of America, 106(34), 14391–14396. https://doi.org/10.1073/pnas.0907357106
Beziaud, L., Mansi, L., Ravel, P., Marie-Joseph, E. L., Laheurte, C., Rangan, L., Bonnefoy, F., Pallandre, J. R., Boullerot, L., Gamonet, C., Vrecko, S., Queiroz, L., Maurina, T., Mouillet, G., Hon, T. N., Curtit, E., Royer, B., Gaugler, B., Bayry, J., … Adotevi, O. (2016). Rapalogs efficacy relies on the modulation of antitumor T-cell immunity. Cancer Research, 76(14), 4100–4112. https://doi.org/10.1158/0008-5472.Can-15-2452
Birle, D. C., & Hedley, D. W. (2007). Suppression of the HIF-1α response in cervical carcinoma xenografts by proteasome inhibitors. Cancer Research, 67(4), 1735–1743. https://doi.org/10.1158/0008-5472.Can-06-2722
Blengio, F., Raggi, F., Pierobon, D., Cappello, P., Eva, A., Giovarelli, M., Varesio, L., & Bosco, M. C. (2013). The hypoxic environment reprograms the cytokine/chemokine expression profile of human mature dendritic cells. Immunobiology, 218(1), 76–89. https://doi.org/10.1016/j.imbio.2012.02.002
Bristow, R. G., & Hill, R. P. (2008). Hypoxia and metabolism: Hypoxia, DNA repair and genetic instability. Nature Reviews Cancer, 8(3), 180–192. https://doi.org/10.1038/nrc2344
Brugarolas, J. (2007). Renal-cell carcinoma--molecular pathways and therapies. New England Journal of Medicine, 356(2), 185–187. https://doi.org/10.1056/NEJMe068263
Bruick, R. K., & McKnight, S. L. (2001). A conserved family of prolyl-4-hydroxylases that modify HIF. Science, 294(5545), 1337–1340. https://doi.org/10.1126/science.1066373
Burslem, G. M., Kyle, H. F., Breeze, A. L., Edwards, T. A., Nelson, A., Warriner, S. L., & Wilson, A. J. (2014). Small-molecule proteomimetic inhibitors of the HIF-1α-p300 protein-protein interaction. ChemBioChem, 15(8), 1083–1087. https://doi.org/10.1002/cbic.201400009
Cairns, R. A., Papandreou, I., Sutphin, P. D., & Denko, N. C. (2007). Metabolic targeting of hypoxia and HIF-1α in solid tumors can enhance cytotoxic chemotherapy. Proceedings of the National Academy of Sciences of the United States of America, 104(22), 9445–9450. https://doi.org/10.1073/pnas.0611662104
Carmeliet, P., & Jain, R. K. (2000). Angiogenesis in cancer and other diseases. Nature, 407(6801), 249–257. https://doi.org/10.1038/35025220
Chang, C. H., Qiu, J., O’Sullivan, D., Buck, M. D., Noguchi, T., Curtis, J. D., Chen, Q., Gindin, M., Gubin, M. M., van der Windt, G. J., Tonc, E., Schreiber, R. D., Pearce, E. J., & Pearce, E. L. (2015). Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell, 162(6), 1229–1241. https://doi.org/10.1016/j.cell.2015.08.016
Chang, Y. L., Yang, C. Y., Lin, M. W., Wu, C. T., & Yang, P. C. (2016). High co-expression of PD-L1 and HIF-1α correlates with tumour necrosis in pulmonary pleomorphic carcinoma. European Journal of Cancer, 60, 125–135. https://doi.org/10.1016/j.ejca.2016.03.012
Chapman-Smith, A., Lutwyche, J. K., & Whitelaw, M. L. (2004). Contribution of the Per/Arnt/Sim (PAS) domains to DNA binding by the basic helix-loop-helix PAS transcriptional regulators. Journal of Biological Chemistry, 279(7), 5353–5362. https://doi.org/10.1074/jbc.M310041200
Chen, W., Lin, C., Gao, Z., Huang, Y., Wang, X., Zhang, Q., Zhang, Y., Tan, M., & Hou, Z. (2025). A tumor microenvironment-responsive nanocomposite for enhanced copper retention and hypoxia reversal to promote cuproptosis in tumor treatment. Acta Biomaterialia, 202, 463–475. https://doi.org/10.1016/j.actbio.2025.07.013
Chen, Z., Han, F., Du, Y., Shi, H., & Zhou, W. (2023). Hypoxic microenvironment in cancer: Molecular mechanisms and therapeutic interventions. Signal Transduction and Targeted Therapy, 8(1). https://doi.org/10.1038/s41392-023-01332-8
Cho, H., Du, X., Rizzi, J. P., Liberzon, E., Chakraborty, A. A., Gao, W., Carvo, I., Signoretti, S., Bruick, R. K., Josey, J. A., Wallace, E. M., & Kaelin, W. G. (2016). On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models. Nature, 539(7627), 107–111. https://doi.org/10.1038/nature19795
Choueiri, T. K., Bauer, T. M., Papadopoulos, K. P., Plimack, E. R., Merchan, J. R., McDermott, D. F., Michaelson, M. D., Appleman, L. J., Thamake, S., Perini, R. F., Zojwalla, N. J., & Jonasch, E. (2021). Inhibition of HIF-2α in renal cell carcinoma with belzutifan: A phase 1 trial and biomarker analysis. Nature Medicine, 27(5), 802–805. https://doi.org/10.1038/s41591-021-01324-7
Chua, Y. S., Chua, Y. L., & Hagen, T. (2010). Structure activity analysis of 2-methoxyestradiol analogues reveals targeting of microtubules as the major mechanism of antiproliferative and proapoptotic activity. Molecular Cancer Therapeutics, 9(1), 224–235. https://doi.org/10.1158/1535-7163.Mct-09-1003
Clambey, E. T., McNamee, E. N., Westrich, J. A., Glover, L. E., Campbell, E. L., Jedlicka, P., de Zoeten, E. F., Cambier, J. C., Stenmark, K. R., Colgan, S. P., & Eltzschig, H. K. (2012). HIF- 1α-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proceedings of the National Academy of Sciences of the United States of America, 109(41), E2784–E2793. https://doi.org/10.1073/pnas.1202366109
Cockman, M. E., Masson, N., Mole, D. R., Jaakkola, P., Chang, G. W., Clifford, S. C., Maher, E. R., Pugh, C. W., Ratcliffe, P. J., & Maxwell, P. H. (2000). HIF-α binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. Journal of Biological Chemistry, 275(33), 25733–25741. https://doi.org/10.1074/jbc.M002740200
Codo, A. C., Davanzo, G. G., Monteiro, L. B., de Souza, G. F., Muraro, S. P., Virgilio-da-Silva, J. V., Prodonoff, J. S., Carregari, V. C., de Biagi Junior, C. A. O., Crunfli, F., Jimenez Restrepo, J. L., Vendramini, P. H., Reis-de-Oliveira, G., Bispo Dos Santos, K., Toledo-Teixeira, D. A., Parise, P. L., Martini, M. C., Marques, R. E., Carmo, H. R., … Moraes-Vieira, P. M. (2020). Elevated glucose levels favor SARSCoV-2 infection and monocyte response through a HIF-1α/glycolysis-dependent axis. Cell Metabolism, 32(3), 437–446.e5. https://doi.org/10.1016/j.cmet.2020.07.007
Corzo, C. A., Condamine, T., Lu, L., Cotter, M. J., Youn, J. I., Cheng, P., Cho, H. I., Celis, E., Quiceno, D. G., Padhya, T., McCaffrey, T. V., McCaffrey, J. C., & Gabrilovich, D. I. (2010). HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. Journal of Experimental Medicine, 207(11), 2439–2453. https://doi.org/10.1084/jem.20100587
Courtney, K. D., Ma, Y., Diaz de Leon, A., Christie, A., Xie, Z., Woolford, L., Singla, N., Joyce, A., Hill, H., Madhuranthakam, A. J., Yuan, Q., Xi, Y., Zhang, Y., Chang, J., Fatunde, O., Arriaga, Y., Frankel, A. E., Kalva, S., Zhang, S., … Brugarolas, J. (2020). HIF-2α complex dissociation, target inhibition, and acquired resistance with PT2385, a first-in-class HIF-2α inhibitor, in patients with clear cell renal cell carcinoma. Clinical Cancer Research, 26(4), 793–803. https://doi.org/10.1158/1078-0432.Ccr-19-1459
Cowman, S. J., & Koh, M. Y. (2022). Revisiting the HIF switch in the tumor and its immune microenvironment. Trends in Cancer, 8(1), 28–42. https://doi.org/10.1016/j.trecan.2021.10.004
Cramer, T., Yamanishi, Y., Clausen, B. E., Forster, I., Pawlinski, R., Mackman, N., Haase, V. H., Jaenisch, R., Corr, M., Nizet, V., Firestein, G. S., Gerber, H. P., Ferrara, N., & Johnson, R. S. (2003). HIF-1α is essential for myeloid cell-mediated inflammation. Cell, 112(5), 645–657. https://doi.org/10.1016/s0092-8674(03)00154-5
Cui, H., Qin, Q., Yang, M., Zhang, H., Liu, Z., Yang, Y., Chen, X., Zhu, H., Wang, D., Meng, C., Song, H., Ma, J., Huang, G., Cai, J., Sun, X., & Wang, Z. (2015). Bortezomib enhances the radiosensitivity of hypoxic cervical cancer cells by inhibiting HIF-1α expression. International Journal of Clinical and Experimental Pathology, 8(8), 9032–9041.
Dang, B., Gao, Q., Zhang, L., Zhang, J., Cai, H., Zhu, Y., Zhong, Q., Liu, J., Niu, Y., Mao, K., Xiao, N., Liu, W. H., Lin, S. H., Huang, J., Huang, S. C., Ho, P. C., & Cheng, S. C. (2023). The glycolysis/HIF-1α axis defines the inflammatory role of IL-4-primed macrophages. Cell Reports, 42(5), 112471. https://doi.org/10.1016/j.celrep.2023.112471
Ding, X., Huang, R., Zhong, Y., Cui, N., Wang, Y., Weng, J., Chen, L., & Zang, M. (2020). CTHRC1 promotes gastric cancer metastasis via HIF-1α/CXCR4 signaling pathway. Biomedicine & Pharmacotherapy, 123, 109742. https://doi.org/10.1016/j.biopha.2019.109742
Doedens, A. L., Stockmann, C., Rubinstein, M. P., Liao, D., Zhang, N., DeNardo, D. G., Coussens, L. M., Karin, M., Goldrath, A. W., & Johnson, R. S. (2010). Macrophage expression of HIF-1α suppresses T-cell function and promotes tumor progression. Cancer Research, 70(19), 7465–7475. https://doi.org/10.1158/0008-5472.Can-10-1439
Escuin, D., Kline, E. R., & Giannakakou, P. (2005). Both microtubule-stabilizing and microtubule-destabilizing drugs inhibit HIF-1α accumulation and activity by disrupting microtubule function. Cancer Research, 65(19), 9021–9028. https://doi.org/10.1158/0008-5472.Can-04-4095
Espinoza, F. I., Tankov, S., Chliate, S., Pereira Couto, J., Marinari, E., Vermeil, T., Lecoultre, M., El Harane, N., Dutoit, V., Migliorini, D., & Walker, P. R. (2025). Targeting HIF-2α in glioblastoma reshapes the immune infiltrate and enhances response to immune checkpoint blockade. Cellular and Molecular Life Sciences, 82(1). https://doi.org/10.1007/s00018-025-05642-8
Estephan, H., Tailor, A., Parker, R., Kreamer, M., Papandreou, I., Campo, L., Easton, A., Moon, E. J., Denko, N. C., Ternette, N., Hammond, E. M., & Giaccia, A. J. (2025). Hypoxia promotes tumor immune evasion by suppressing MHC-I expression and antigen presentation. EMBO Journal, 44(3), 903–922. https://doi.org/10.1038/s44318-024-00319-7
Feng, Z., Zou, X., Chen, Y., Wang, H., Duan, Y., & Bruick, R. K. (2018). Modulation of HIF-2α PAS-B domain contributes to physiological responses. Proceedings of the National Academy of Sciences of the United States of America, 115(52), 13240–13245. https://doi.org/10.1073/pnas.1810897115
Fischer, K., Hoffmann, P., Voelkl, S., Meidenbauer, N., Ammer, J., Edinger, M., Gottfried, E., Schwarz, S., Rothe, G., Hoves, S., Renner, K., Timischl, B., Mackensen, A., Kunz-Schughart, L., Andreesen, R., Krause, S. W., & Kreutz, M. (2007). Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood, 109(9), 3812–3819. https://doi.org/10.1182/blood-2006-07-035972
Freedman, S. J., Sun, Z. Y., Poy, F., Kung, A. L., Livingston, D. M., Wagner, G., & Eck, M. J. (2002). Structural basis for recruitment of CBP/p300 by HIF-1α. Proceedings of the National Academy of Sciences of the United States of America, 99(8), 5367–5372. https://doi.org/10.1073/pnas.082117899
Gameiro, P. A., Yang, J., Metelo, A. M., Perez-Carro, R., Baker, R., Wang, Z., Arreola, A., Rathmell, W. K., Olumi, A., Lopez-Larrubia, P., Stephanopoulos, G., & Iliopoulos, O. (2013). In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation. Cell Metabolism, 17(3), 372–385. https://doi.org/10.1016/j.cmet.2013.02.002
Garcia Garcia, C. J., Huang, Y., Fuentes, N. R., Turner, M. C., Monberg, M. E., Lin, D., Nguyen, N. D., Fujimoto, T. N., Zhao, J., Lee, J. J., Bernard, V., Yu, M., Delahoussaye, A. M., Jimenez Sacarello, I., Caggiano, E. G., Phan, J. L., Deorukhkar, A., Molkentine, J. M., Saur, D., … Taniguchi, C. M. (2022). Stromal HIF-2α regulates immune suppression in the pancreatic cancer microenvironment. Gastroenterology, 162(7), 2018–2031. https://doi.org/10.1053/j.gastro.2022.02.024
Guo, X., Xue, H., Shao, Q., Wang, J., Guo, X., Chen, X., Zhang, J., Xu, S., Li, T., Zhang, P., Gao, X., Qiu, W., Liu, Q., & Li, G. (2016). Hypoxia promotes glioma-associated macrophage infiltration via periostin and subsequent M2 polarization by upregulating TGF-beta and M-CSFR. Oncotarget, 7(49), 80521–80542. https://doi.org/10.18632/oncotarget.11825
Hajizadeh, F., Moghadaszadeh Ardebili, S., Baghi Moornani, M., Masjedi, A., Atyabi, F., Kiani, M., Namdar, A., Karpisheh, V., Izadi, S., Baradaran, B., Azizi, G., Ghalamfarsa, G., Sabz, G., Yousefi, M., & Jadidi-Niaragh, F. (2020). Silencing of HIF-1α/CD73 axis by siRNA-loaded TATchitosan-spion nanoparticles robustly blocks cancer cell progression. European Journal of Pharmacology, 882, 173235. https://doi.org/10.1016/j.ejphar.2020.173235
Hallis, S. P., Kim, S. K., Lee, J. H., & Kwak, M. K. (2023). Association of NRF2 with HIF-2α-induced cancer stem cell phenotypes in chronic hypoxic condition. Redox Biology, 60, 102632. https://doi.org/10.1016/j.redox.2023.102632
Hamzah, J., Jugold, M., Kiessling, F., Rigby, P., Manzur, M., Marti, H. H., Rabie, T., Kaden, S., Grone, H. J., Hammerling, G. J., Arnold, B., & Ganss, R. (2008). Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature, 453(7193), 410–414. https://doi.org/10.1038/nature06868
Hatfield, S. M., & Sitkovsky, M. (2016). A2A adenosine receptor antagonists to weaken the hypoxia-HIF-1α driven immunosuppression and improve immunotherapies of cancer. Current Opinion in Pharmacology, 29, 90–96. https://doi.org/10.1016/j.coph.2016.06.009
He, H., Liao, Q., Zhao, C., Zhu, C., Feng, M., Liu, Z., Jiang, L., Zhang, L., Ding, X., Yuan, M., Zhang, X., & Xu, J. (2021). Conditioned CAR-T cells by hypoxia-inducible transcription amplification (HiTA) system significantly enhances systemic safety and retains antitumor efficacy. Journal for ImmunoTherapy of Cancer, 9(10), e002755. https://doi.org/10.1136/jitc-2021-002755
Hoefflin, R., Harlander, S., Schafer, S., Metzger, P., Kuo, F., Schonenberger, D., Adlesic, M., Peighambari, A., Seidel, P., Chen, C. Y., Consenza-Contreras, M., Jud, A., Lahrmann, B., Grabe, N., Heide, D., Uhl, F. M., Chan, T. A., Duyster, J., Zeiser, R., … Frew, I. J. (2020). HIF-1α and HIF-2α differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice. Nature Communications, 11(1). https://doi.org/10.1038/s41467-020-17873-3
Holmquist-Mengelbier, L., Fredlund, E., Lofstedt, T., Noguera, R., Navarro, S., Nilsson, H., Pietras, A., Vallon-Christersson, J., Borg, A., Gradin, K., Poellinger, L., & Pahlman, S. (2006). Recruitment of HIF-1α and HIF-2α to common target genes is differentially regulated in neuroblastoma: HIF-2α promotes an aggressive phenotype. Cancer Cell, 10(5), 413–423. https://doi.org/10.1016/j.ccr.2006.08.026
Hsiao, H. W., Hsu, T. S., Liu, W. H., Hsieh, W. C., Chou, T. F., Wu, Y. J., Jiang, S. T., & Lai, M. Z. (2015). Deltex1 antagonizes HIF-1α and sustains the stability of regulatory T cells in vivo. Nature Communications, 6(1). https://doi.org/10.1038/ncomms7353
Hsu, T. S., Lin, Y. L., Wang, Y. A., Mo, S. T., Chi, P. Y., Lai, A. C., Pan, H. Y., Chang, Y. J., & Lai, M. Z. (2020). HIF-2α is indispensable for regulatory T cell function. Nature Communications, 11(1), 5005. https://doi.org/10.1038/s41467-020-18731-y
Hu, C. J., Wang, L. Y., Chodosh, L. A., Keith, B., & Simon, M. C. (2003). Differential roles of HIF-1α and HIF-2α in hypoxic gene regulation. Molecular and Cellular Biology, 23(24), 9361–9374. https://doi.org/10.1128/mcb.23.24.9361-9374.2003
Huang, D., Li, T., Li, X., Zhang, L., Sun, L., He, X., Zhong, X., Jia, D., Song, L., Semenza, G. L., Gao, P., & Zhang, H. (2014). HIF-1-mediated suppression of acyl-CoA dehydrogenases and fatty acid oxidation is critical for cancer progression. Cell Reports, 8(6), 1930–1942. https://doi.org/10.1016/j.celrep.2014.08.028
Imamura, T., Kikuchi, H., Herraiz, M. T., Park, D. Y., Mizukami, Y., Mino-Kenduson, M., Lynch, M. P., Rueda, B. R., Benita, Y., Xavier, R. J., & Chung, D. C. (2009). HIF-1α and HIF-2α have divergent roles in colon cancer. International Journal of Cancer, 124(4), 763–771. https://doi.org/10.1002/ijc.24032
Imtiyaz, H. Z., Williams, E. P., Hickey, M. M., Patel, S. A., Durham, A. C., Yuan, L. J., Hammond, R., Gimotty, P. A., Keith, B., & Simon, M. C. (2010). HIF-2α regulates macrophage function in mouse models of acute and tumor inflammation. Journal of Clinical Investigation, 120(8), 2699–2714. https://doi.org/10.1172/jci39506
Isaacs, J. S., Jung, Y. J., Mimnaugh, E. G., Martinez, A., Cuttitta, F., & Neckers, L. M. (2002). Hsp90 regulates a von Hippel Lindau-independent HIF-1α-degradative pathway. Journal of Biological Chemistry, 277(33), 29936–29944. https://doi.org/10.1074/jbc.M204733200
Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J. M., Lane, W. S., & Kaelin, W. G., Jr. (2001). HIFα targeted for VHL-mediated destruction by proline hydroxylation: Implications for O2 sensing. Science, 292(5516), 464–468. https://doi.org/10.1126/science.1059817
Jaakkola, P., Mole, D. R., Tian, Y. M., Wilson, M. I., Gielbert, J., Gaskell, S. J., von Kriegsheim, A., Hebestreit, H. F., Mukherji, M., Schofield, C. J., Maxwell, P. H., Pugh, C. W., & Ratcliffe, P. J. (2001). Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science, 292(5516), 468–472. https://doi.org/10.1126/science.1059796
Jain, R. K. (2005). Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science, 307(5706), 58–62. https://doi.org/10.1126/science.1104819
Jansen, C. S., Prokhnevska, N., Master, V. A., Sanda, M. G., Carlisle, J. W., Bilen, M. A., Cardenas, M., Wilkinson, S., Lake, R., Sowalsky, A. G., Valanparambil, R. M., Hudson, W. H., McGuire, D., Melnick, K., Khan, A. I., Kim, K., Chang, Y. M., Kim, A., Filson, C. P., … Kissick, H. (2019). An intratumoral niche maintains and differentiates stem-like CD8 T cells. Nature, 576(7787), 465–470. https://doi.org/10.1038/s41586-019-1836-5
Jeong, W., Rapisarda, A., Park, S. R., Kinders, R. J., Chen, A., Melillo, G., Turkbey, B., Steinberg, S. M., Choyke, P., Doroshow, J. H., & Kummar, S. (2014). Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of HIF-1α, in patients with refractory solid tumors. Cancer Chemotherapy and Pharmacology, 73(2), 343–348. https://doi.org/10.1007/s00280-013-2362-z
Jiang, B. H., Rue, E., Wang, G. L., Roe, R., & Semenza, G. L. (1996). Dimerization, DNA binding, and transactivation properties of HIF-1. Journal of Biological Chemistry, 271(30), 17771–17778. https://doi.org/10.1074/jbc.271.30.17771
Jiang, P., Gu, S., Pan, D., Fu, J., Sahu, A., Hu, X., Li, Z., Traugh, N., Bu, X., Li, B., Liu, J., Freeman, G. J., Brown, M. A., Wucherpfennig, K. W., & Liu, X. S. (2018). Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nature Medicine, 24(10), 1550–1558. https://doi.org/10.1038/s41591-018-0136-1
Jiang, W., Huang, Y., An, Y., & Kim, B. Y. (2015). Remodeling tumor vasculature to enhance delivery of intermediate-sized nanoparticles. ACS Nano, 9(9), 8689–8696. https://doi.org/10.1021/acsnano.5b02028
Jonasch, E., Donskov, F., Iliopoulos, O., Rathmell, W. K., Narayan, V. K., Maughan, B. L., Oudard, S., Else, T., Maranchie, J. K., Welsh, S. J., Thamake, S., Park, E. K., Perini, R. F., Linehan, W. M., & Srinivasan, R. (2021). Belzutifan for renal cell carcinoma in von Hippel-Lindau disease. New England Journal of Medicine, 385(22), 2036–2046. https://doi.org/10.1056/nejmoa2103425
Kai, A. K., Chan, L. K., Lo, R. C., Lee, J. M., Wong, C. C., Wong, J. C., & Ng, I. O. (2016). Down-regulation of TIMP2 by HIF-1α/miR-210/HIF-3α regulatory feedback circuit enhances cancer metastasis in hepatocellular carcinoma. Hepatology, 64(2), 473–487. https://doi.org/10.1002/hep.28577
Kaidi, A., Williams, A. C., & Paraskeva, C. (2007). Interaction between beta-catenin and HIF-1α promotes cellular adaptation to hypoxia. Nature Cell Biology, 9(2), 210–217. https://doi.org/10.1038/ncb1534
Kaluz, S., Kaluzova, M., & Stanbridge, E. J. (2008). Regulation of gene expression by hypoxia: Integration of the HIF-transduced hypoxic signal at the hypoxia-responsive element. Clinica Chimica Acta, 395(1-2), 6–13. https://doi.org/10.1016/j.cca.2008.05.002
Kang, S., Onishi, S., Ling, Z., Inoue, H., Zhang, Y., Chang, H., Zhao, H., Wang, T., Okuzaki, D., Matsuura, H., Takamatsu, H., Oda, J., & Kishimoto, T. (2024). Gp130-HIF-1α axis-induced vascular damage is prevented by the short-term inhibition of IL-6 receptor signaling. Proceedings of the National Academy of Sciences of the United States of America, 121(2). https://doi.org/10.1073/pnas.2315898120
Kim, J. W., Evans, C., Weidemann, A., Takeda, N., Lee, Y. S., Stockmann, C., Branco-Price, C., Brandberg, F., Leone, G., Ostrowski, M. C., & Johnson, R. S. (2012). Loss of fibroblast HIF-1α accelerates tumorigenesis. Cancer Research, 72(13), 3187–3195. https://doi.org/10.1158/0008-5472.Can-12-0534
Kim, J. W., Tchernyshyov, I., Semenza, G. L., & Dang, C. V. (2006). HIF-1α-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia. Cell Metabolism, 3(3), 177–185. https://doi.org/10.1016/j.cmet.2006.02.002
Kim, T. H., Hur, E. G., Kang, S. J., Kim, J. A., Thapa, D., Lee, Y. M., Ku, S. K., Jung, Y., & Kwak, M. K. (2011). NRF2 blockade suppresses colon tumor angiogenesis by inhibiting hypoxia-induced activation of HIF-1α. Cancer Research, 71(6), 2260–2275. https://doi.org/10.1158/0008-5472.Can-10-3007
Koh, M. Y., Spivak-Kroizman, T., Venturini, S., Welsh, S., Williams, R. R., Kirkpatrick, D. L., & Powis, G. (2008). Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of HIF-1α. Molecular Cancer Therapeutics, 7(1), 90–100. https://doi.org/10.1158/1535-7163.Mct-07-0463
Kong, D., Park, E. J., Stephen, A. G., Calvani, M., Cardellina, J. H., Monks, A., Fisher, R. J., Shoemaker, R. H., & Melillo, G. (2005). Echinomycin, a small-molecule inhibitor of HIF-1α DNA-binding activity. Cancer Research, 65(19), 9047–9055. https://doi.org/10.1158/0008-5472.Can-05-1235
Kosti, P., Opzoomer, J. W., Larios-Martinez, K. I., Henley-Smith, R., Scudamore, C. L., Okesola, M., Taher, M. Y. M., Davies, D. M., Muliaditan, T., Larcombe-Young, D., Woodman, N., Gillett, C. E., Thavaraj, S., Maher, J., & Arnold, J. N. (2021). Hypoxia-sensing CAR T cells provide safety and efficacy in treating solid tumors. Cell Reports Medicine, 2(4), 100227. https://doi.org/10.1016/j.xcrm.2021.100227
Kumar, V., & Gabrilovich, D. I. (2014). HIFs in regulation of immune responses in tumour microenvironment. Immunology, 143(4), 512–519. https://doi.org/10.1111/imm.12380
Lee, K., Qian, D. Z., Rey, S., Wei, H., Liu, J. O., & Semenza, G. L. (2009a). Anthracycline chemotherapy inhibits HIF-1α transcriptional activity and tumor-induced mobilization of circulating angiogenic cells. Proceedings of the National Academy of Sciences of the United States of America, 106(7), 2353–2358. https://doi.org/10.1073/pnas.0812801106
Lee, K., Zhang, H., Qian, D. Z., Rey, S., Liu, J. O., & Semenza, G. L. (2009b). Acriflavine inhibits HIF-1α dimerization, tumor growth, and vascularization. Proceedings of the National Academy of Sciences of the United States of America, 106(42), 17910–17915. https://doi.org/10.1073/pnas.0909353106
Lee, K. M., Giltnane, J. M., Balko, J. M., Schwarz, L. J., Guerrero-Zotano, A. L., Hutchinson, K. E., Nixon, M. J., Estrada, M. V., Sanchez, V., Sanders, M. E., Lee, T., Gomez, H., Lluch, A., Perez-Fidalgo, J. A., Wolf, M. M., Andrejeva, G., Rathmell, J. C., Fesik, S. W., & Arteaga, C. L. (2017). MYC and MCL1 cooperatively promote chemotherapy-resistant breast cancer stem cells via regulation of mitochondrial oxidative phosphorylation. Cell Metabolism, 26(4), 633–647.e7. https://doi.org/10.1016/j.cmet.2017.09.009
Lee, W. S., Yang, H., Chon, H. J., & Kim, C. (2020). Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity. Experimental & Molecular Medicine, 52(9), 1475–1485. https://doi.org/10.1038/s12276-020-00500-y
Lequeux, A., Noman, M. Z., Xiao, M., Van Moer, K., Hasmim, M., Benoit, A., Bosseler, M., Viry, E., Arakelian, T., Berchem, G., Chouaib, S., & Janji, B. (2021). Targeting HIF-1α transcriptional activity drives cytotoxic immune effector cells into melanoma and improves combination immunotherapy. Oncogene, 40(28), 4725–4735. https://doi.org/10.1038/s41388-021-01846-x
Li, C. Y., Shan, S., Huang, Q., Braun, R. D., Lanzen, J., Hu, K., Lin, P., & Dewhirst, M. W. (2000). Initial stages of tumor cell-induced angiogenesis: Evaluation via skin window chambers in rodent models. Journal of the National Cancer Institute, 92(2), 143–147. https://doi.org/10.1093/jnci/92.2.143
Li, Y., Zhu, R., He, X., Song, Y., Fan, T., Ma, J., Xiang, G., & Ma, X. (2024). Discovery of potent HIF-1α degraders by proteolysis targeting chimera (PROTAC). Bioorganic Chemistry, 153, 107943. https://doi.org/10.1016/j.bioorg.2024.107943
Lin, S., Chai, Y., Zheng, X., & Xu, X. (2023). The role of HIF in angiogenesis, lymphangiogenesis, and tumor microenvironment in urological cancers. Molecular Biology Reports, 51(1). https://doi.org/10.1007/s11033-023-08931-2
Liu, J., Jiang, Y., Chen, L., Qian, Z., & Zhang, Y. (2024). Associations between HIFs and tumor immune checkpoints: Mechanism and therapy. Discover Oncology, 15(1). https://doi.org/10.1007/s12672-023-00836-7
Liu, S., Liu, X., Zhang, C., Shan, W., & Qiu, X. (2021). T-cell exhaustion status under high and low levels of HIF-1α expression in glioma. Frontiers in Pharmacology, 12. https://doi.org/10.3389/fphar.2021.711772
Liu, W., Dou, C., Zhang, C., Chen, P., Zhang, S., Wang, R., Han, Q., Zhao, H., & Li, D. (2024). PX-478 induces apoptosis in acute myeloid leukemia under hypoxia by inhibiting the PI3K/AKT/mTOR pathway through downregulation of GBE1. Biochemical Pharmacology, 230, 116620. https://doi.org/10.1016/j.bcp.2024.116620
Liu, Y., Cox, S. R., Morita, T., & Kourembanas, S. (1995). Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells: Identification of a 5› enhancer. Circulation Research, 77(3), 638–643. https://doi.org/10.1161/01.res.77.3.638
Lu, Y., Wang, B., Shi, Q., Wang, X., Wang, D., & Zhu, L. (2016). Brusatol inhibits HIF-1 signaling pathway and suppresses cells. Scientific Reports, 6(1). https://doi.org/10.1038/srep39123
Luo, Z., Tian, M., Yang, G., Tan, Q., Chen, Y., Li, G., Zhang, Q., Li, Y., Wan, P., & Wu, J. (2022). Hypoxia signaling in human health and diseases: Implications and prospects for therapeutics. Signal Transduction and Targeted Therapy, 7(1). https://doi.org/10.1038/s41392-022-01080-1
Ma, S., Zhao, Y., Lee, W. C., Ong, L.-T., Lee, P. L., Jiang, Z., Oguz, G., Niu, Z., Liu, M., Goh, J. Y., Wang, W., Bustos, M. A., Ehmsen, S., Ramasamy, A., Hoon, D. S. B., Ditzel, H. J., Tan, E. Y., Chen, Q., & Yu, Q. (2022). Hypoxia induces HIF1α-dependent epigenetic vulnerability in triple-negative breast cancer to confer immune effector dysfunction and resistance to anti-PD-1 immunotherapy. Nature Communications, 13(1). https://doi.org/10.1038/s41467-022-31764-9
Mahon, P. C., Hirota, K., & Semenza, G. L. (2001). FIH-1: A novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1α transcriptional activity. Genes & Development, 15(20), 2675–2686. https://doi.org/10.1101/gad.924501
Makino, Y., Kanopka, A., Wilson, W. J., Tanaka, H., & Poellinger, L. (2002). Inhibitory PAS domain protein (IPAS) is a hypoxia-inducible splicing variant of the HIF-3α locus. Journal of Biological Chemistry, 277(36), 32405–32408. https://doi.org/10.1074/jbc.C200328200
Mal, A., Xie, B., Gray, Z., Small, C., Ramanand, S. G., Gao, Y., Toffessi Tcheuyap, V., Debnath, S., Christie, A., Miyata, J., Jackson, B., Zhong, H., Gao, B., Lohrey, J., Maalouf, N. M., Reddy, S. M., Minna, J. D., Pedrosa, I., Sun, X., … Brugarolas, J. (2025). HIF-2α-dependent regulation of PTHrP and paraneoplastic hypercalcemia in aggressive clear-cell renal cell carcinoma. Cancer Discovery, 15(12), 2485–2504. https://doi.org/10.1158/2159-8290.Cd-25-0638
Mangraviti, A., Raghavan, T., Volpin, F., Skuli, N., Gullotti, D., Zhou, J., Asnaghi, L., Sankey, E., Liu, A., Wang, Y., Lee, D.-H., Gorelick, N., Serra, R., Peters, M., Schriefer, D., Delaspre, F., Rodriguez, F. J., Eberhart, C. G., Brem, H., …Tyler, B. (2017). HIF-1α-targeting acriflavine provides long term survival and radiological tumor response in brain cancer therapy. Scientific Reports, 7(1). https://doi.org/10.1038/s41598-017-14990-w
Michiels, C., Tellier, C., & Feron, O. (2016). Cycling hypoxia: A key feature of the tumor microenvironment. *Biochimica et Biophysica Acta - Reviews on Cancer, 1866*(1), 76–86. https://doi.org/10.1016/j.bbcan.2016.06.004
Mimeault, M., & Batra, S. K. (2013). Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells. Journal of Cellular and Molecular Medicine, 17(1), 30–54. https://doi.org/10.1111/jcmm.12004
Mira, E., Carmona-Rodriguez, L., Perez-Villamil, B., Casas, J., Fernandez-Acenero, M. J., Martinez-Rey, D., Martin-Gonzalez, P., Heras-Murillo, I., Paz-Cabezas, M., Tardaguila, M., Oury, T. D., Martin-Puig, S., Lacalle, R. A., Fabrias, G., Diaz-Rubio, E., & Manes, S. (2018). SOD3 improves the tumor response to chemotherapy by stabilizing endothelial HIF-2α. Nature Communications, 9(1). https://doi.org/10.1038/s41467-018-03079-1
Miranda, E., Nordgren, I. K., Male, A. L., Lawrence, C. E., Hoakwie, F., Cuda, F., Court, W., Fox, K. R., Townsend, P. A., Packham, G. K., Eccles, S. A., & Tavassoli, A. (2013). A cyclic peptide inhibitor of HIF-1α heterodimerization that inhibits hypoxia signaling in cancer cells. Journal of the American Chemical Society, 135(28), 10418–10425. https://doi.org/10.1021/ja402993u
Miska, J., Lee-Chang, C., Rashidi, A., Muroski, M. E., Chang, A. L., Lopez-Rosas, A., Zhang, P., Panek, W. K., Cordero, A., Han, Y., Ahmed, A. U., Chandel, N. S., & Lesniak, M. S. (2022). HIF-1α is a metabolic switch between glycolytic-driven migration and oxidative phosphorylation-driven immunosuppression of Tregs in glioblastoma. Cell Reports, 39(10), 110934. https://doi.org/10.1016/j.celrep.2022.110934
Missiaen, R., Lesner, N. P., & Simon, M. C. (2023). HIF: A master regulator of nutrient availability and metabolic cross-talk in the tumor microenvironment. EMBO Journal, 42(6). https://doi.org/10.15252/embj.2022112067
Moon, E. J., Mello, S. S., Li, C. G., Chi, J. T., Thakkar, K., Kirkland, J. G., Lagory, E. L., Lee, I. J., Diep, A. N., Miao, Y., Rafat, M., Vilalta, M., Castellini, L., Krieg, A. J., Graves, E. E., Attardi, L. D., & Giaccia, A. J. (2021). The HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling. Nature Communications, 12(1). https://doi.org/10.1038/s41467-021-24631-6
Mpekris, F., Voutouri, C., Baish, J. W., Duda, D. G., Munn, L. L., Stylianopoulos, T., & Jain, R. K. (2020). Combining microenvironment normalization strategies to improve cancer immunotherapy. Proceedings of the National Academy of Sciences of the United States of America, 117(7), 3728–3737. https://doi.org/10.1073/pnas.1919764117
Nakazawa, T., Morimoto, T., Maeoka, R., Yamada, K., Matsuda, R., Nakamura, M., Nishimura, F., Yamada, S., Park, Y. S., Tsujimura, T., & Nakagawa, I. (2024). Characterization of HIF-1α knockout primary human natural killer cells including populations in allogeneic glioblastoma. International Journal of Molecular Sciences, 25(11), 5896. https://doi.org/10.3390/ijms25115896
Naldini, A., Morena, E., Pucci, A., Pellegrini, M., Baldari, C. T., Pelicci, P. G., Presta, M., Ribatti, D., & Carraro, F. (2010). The adaptor protein p66Shc is a positive regulator in the angiogenic response induced by hypoxic T cells. Journal of Leukocyte Biology, 87(3), 365–369. https://doi.org/10.1189/jlb.0709460
Neelapu, S. S., Locke, F. L., Bartlett, N. L., Lekakis, L. J., Miklos, D. B., Jacobson, C. A., Braunschweig, I., Oluwole, O. O., Siddiqi, T., Lin, Y., Timmerman, J. M., Stiff, P. J., Friedberg, J. W., Flinn, I. W., Goy, A., Hill, B. T., Smith, M. R., Deol, A., Farooq, U., … Go, W. Y. (2017). Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. New England Journal of Medicine, 377(26), 2531–2544. https://doi.org/10.1056/NEJMoa1707447
Ni, J., Wang, X., Stojanovic, A., Zhang, Q., Wincher, M., Buhler, L., Arnold, A., Correia, M. P., Winkler, M., Koch, P. S., Sexl, V., Hofer, T., & Cerwenka, A. (2020). Single-cell RNA sequencing of tumor-infiltrating NK cells reveals that inhibition of transcription factor HIF-1α unleashes NK cell activity. Immunity, 52(6), 1075–1087.e8. https://doi.org/10.1016/j.immuni.2020.05.001
Nicolini, A., & Ferrari, P. (2024). Involvement of tumor immune microenvironment metabolic reprogramming in colorectal cancer progression, immune escape, and response to immunotherapy. Frontiers in Immunology, 15. https://doi.org/10.3389/fimmu.2024.1353787
Ning, F., Takeda, K., Schedel, M., Domenico, J., Joetham, A., & Gelfand, E. W. (2019). Hypoxia enhances CD8+ T(C)2 cell-dependent airway hyperresponsiveness and inflammation through HIF-1α. Journal of Allergy and Clinical Immunology, 143(6), 2026–2037.e7. https://doi.org/10.1016/j.jaci.2018.11.049
Niu, Y., Chen, Y., Sun, P., Wang, Y., Luo, J., Ding, Y., & Xie, W. (2021). Intragastric and atomized administration of canagliflozin inhibit inflammatory cytokine storm in lipopolysaccharide-treated sepsis in mice: A potential COVID-19 treatment. International Immunopharmacology, 96, 107773. https://doi.org/10.1016/j.intimp.2021.107773
Noman, M. Z., Desantis, G., Janji, B., Hasmim, M., Karray, S., Dessen, P., Bronte, V., & Chouaib, S. (2014). PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. Journal of Experimental Medicine, 211(5), 781–790. https://doi.org/10.1084/jem.20131916
Obeagu, E. I. (2025). Hypoxia-driven angiogenesis in breast cancer mechanisms and therapeutic targets: A narrative review. Annals of Medicine & Surgery, 87(7), 4246–4254. https://doi.org/10.1097/ms9.0000000000003411
Oh, E. T., Kim, C. W., Kim, H. G., Lee, J. S., & Park, H. J. (2017). Brusatol-mediated inhibition of c-Myc increases HIF-1α degradation and causes cell death in colorectal cancer under hypoxia. Theranostics, 7(14), 3415–3431. https://doi.org/10.7150/thno.20861
Palazon, A., Tyrakis, P. A., Macias, D., Velica, P., Rundqvist, H., Fitzpatrick, S., Vojnovic, N., Phan, A. T., Loman, N., Hedenfalk, I., Hatschek, T., Lovrot, J., Foukakis, T., Goldrath, A. W., Bergh, J., & Johnson, R. S. (2017). An HIF-1α/VEGF-A axis in cytotoxic T cells regulates tumor progression. Cancer Cell, 32(5), 669–683.e5. https://doi.org/10.1016/j.ccell.2017.10.003
Park, J. S., Kim, I. K., Han, S., Park, I., Kim, C., Bae, J., Oh, S. J., Lee, S., Kim, J. H., Woo, D. C., He, Y., Augustin, H. G., Kim, I., Lee, D., & Koh, G. Y. (2016). Normalization of tumor vessels by Tie2 activation and Ang2 inhibition enhances drug delivery and produces a favorable tumor microenvironment. Cancer Cell, 30(6), 953–967. https://doi.org/10.1016/j.ccell.2016.10.018
Partch, C. L., & Gardner, K. H. (2011). Coactivators necessary for transcriptional output of the hypoxia inducible factor, HIF, are directly recruited by ARNT PAS-B. Proceedings of the National Academy of Sciences of the United States of America, 108(19), 7739–7744. https://doi.org/10.1073/pnas.1101357108
Peng, H., Yao, F., Zhao, J., Zhang, W., Chen, L., Wang, X., Yang, P., Tang, J., & Chi, Y. (2023). Unraveling mitochondria-targeting reactive oxygen species modulation and their implementations in cancer therapy by nanomaterials. Exploration, 3(2). https://doi.org/10.1002/exp.20220115
Powles, T., Albiges, L., & Rini, B. (2024). Belzutifan versus everolimus for advanced renal-cell carcinoma: Reply. New England Journal of Medicine, 391(21), 2062–2063. https://doi.org/10.1056/NEJMc2411843
Qannita, R. A., Alalami, A. I., Harb, A. A., Aleidi, S. M., Taneera, J., Abu-Gharbieh, E., El-Huneidi, W., Saleh, M. A., Alzoubi, K. H., Semreen, M. H., Hudaib, M., & Bustanji, Y. (2024). Targeting HIF-1α in cancer: Emerging therapeutic strategies and pathway regulation. Pharmaceuticals, 17(2), 195. https://doi.org/10.3390/ph17020195
Riley, J. L. (2009). PD-1 signaling in primary T cells. Immunological Reviews, 229(1), 114–125. https://doi.org/10.1111/j.1600-065X.2009.00767.x
Rohwer, N., Jumpertz, S., Erdem, M., Egners, A., Warzecha, K. T., Fragoulis, A., Kuhl, A. A., Kramann, R., Neuss, S., Rudolph, I., Endermann, T., Zasada, C., Apostolova, I., Gerling, M., Kempa, S., Hughes, R., Lewis, C. E., Brenner, W., Malinowski, M. B., … Cramer, T. (2019). Noncanonical HIF-1α stabilization contributes to intestinal tumorigenesis. Oncogene, 38(28), 5670–5685. https://doi.org/10.1038/s41388-019-0816-4
Ryan, H. E., Poloni, M., McNulty, W., Elson, D., Gassmann, M., Arbeit, J. M., & Johnson, R. S. (2000). HIF-1α is a positive factor in solid tumor growth. Cancer Research, 60(15), 4010–4015.
Salceda, S., & Caro, J. (1997). HIF-1α protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions: Its stabilization by hypoxia depends on redox-induced changes. Journal of Biological Chemistry, 272(36), 22642–22647. https://doi.org/10.1074/jbc.272.36.22642
Scheuermann, T. H., Li, Q., Ma, H. W., Key, J., Zhang, L., Chen, R., Garcia, J. A., Naidoo, J., Longgood, J., Frantz, D. E., Tambar, U. K., Gardner, K. H., & Bruick, R. K. (2013). Allosteric inhibition of HIF-2α with small molecules. Nature Chemical Biology, 9(4), 271–276. https://doi.org/10.1038/nchembio.1185
Semenza, G. L. (2002). HIF-1α and tumor progression: Pathophysiology and therapeutics. Trends in Molecular Medicine, 8(4), S62–S67. https://doi.org/10.1016/s1471-4914(02)02317-1
Semenza, G. L. (2012). HIFs in physiology and medicine. Cell, 148(3), 399–408. https://doi.org/10.1016/j.cell.2012.01.021
Semenza, G. L. (2013). HIF-1α mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. Journal of Clinical Investigation, 123(9), 3664–3671. https://doi.org/10.1172/jci67230
Semenza, G. L. (2021). Intratumoral hypoxia and mechanisms of immune evasion mediated by hypoxia-inducible factors. Physiology, 36(2), 73–83. https://doi.org/10.1152/physiol.00034.2020
Semenza, G. L., Agani, F., Booth, G., Forsythe, J., Iyer, N., Jiang, B. H., Leung, S., Roe, R., Wiener, C., & Yu, A. (1997). Structural and functional analysis of HIF-1. Kidney International, 51(2), 553–555. https://doi.org/10.1038/ki.1997.77
Semenza, G. L., Nejfelt, M. K., Chi, S. M., & Antonarakis, S. E. (1991). Hypoxia-inducible nuclear factors bind to an enhancer element located 3› to the human erythropoietin gene. Proceedings of the National Academy of Sciences of the United States of America, 88(13), 5680–5684. https://doi.org/10.1073/pnas.88.13.5680
Shen, H., Ojo, O. A., Ding, H., Mullen, L. J., Xing, C., Hossain, M. I., Yassin, A., Shi, V. Y., Lewis, Z., Podgorska, E., Andrabi, S. A., Antoniewicz, M. R., Bonner, J. A., & Shi, L. Z. (2024). HIF1α-regulated glycolysis promotes activation-induced cell death and IFN-γ induction in hypoxic T cells. Nature Communications, 15(1). https://doi.org/10.1038/s41467-024-53593-8
Shin, S., Choi, Y., Jang, W., Ulziituya, B., Ha, G., Kang, R., Park, S., Kim, M., Zhang, Y. S., Kim, H. J., & Lee, J. (2025). A vascularized tumors-on-a-chip model for studying tumor-angiogenesis interplay, heterogeneity and drug responses. Materials Today Bio, 32, 101741. https://doi.org/10.1016/j.mtbio.2025.101741
Song, S., Zhang, Y., Duan, X., Liu, C., Du, Y., Wang, X., Luo, Y., & Cui, Y. (2023). HIF-1α/IL-8 axis in hypoxic macrophages promotes esophageal cancer progression by enhancing PD-L1 expression. Cancer Gene Therapy, 30(2), 358–367. https://doi.org/10.1038/s41417-022-00551-5
Sullivan, R., Pare, G. C., Frederiksen, L. J., Semenza, G. L., & Graham, C. H. (2008). Hypoxia-induced resistance to anticancer drugs is associated with decreased senescence and requires HIF-1α activity. Molecular Cancer Therapeutics, 7(7), 1961–1973. https://doi.org/10.1158/1535-7163.Mct-08-0198
Sun, R. C., & Denko, N. C. (2014). Hypoxic regulation of glutamine metabolism through HIF-1α and SIAH2 supports lipid synthesis that is necessary for tumor growth. Cell Metabolism, 19(2), 285–292. https://doi.org/10.1016/j.cmet.2013.11.022
Sun, X., Wei, L., Chen, Q., & Terek, R. M. (2010). CXCR4/SDF1 mediate hypoxia induced chondrosarcoma cell invasion through ERK signaling and increased MMP1 expression. Molecular Cancer, 9(1). https://doi.org/10.1186/1476-4598-9-17
Susen, R. M., Bauer, R., Olesch, C., Fuhrmann, D. C., Fink, A. F., Dehne, N., Jain, A., Ebersberger, I., Schmid, T., & Brune, B. (2019). Macrophage HIF-2α regulates tumor-suppressive Spint1 in the tumor microenvironment. Molecular Carcinogenesis, 58(11), 2127–2138. https://doi.org/10.1002/mc.23103
Takeda, N., O’Dea, E. L., Doedens, A., Kim, J. W., Weidemann, A., Stockmann, C., Asagiri, M., Simon, M. C., Hoffmann, A., & Johnson, R. S. (2010). Differential activation and antagonistic function of HIF-α isoforms in macrophages are essential for NO homeostasis. Genes & Development, 24(5), 491–501. https://doi.org/10.1101/gad.1881410
Tanaka, T., Yamaguchi, J., Shoji, K., & Nangaku, M. (2012). Anthracycline inhibits recruitment of hypoxia-inducible transcription factors and suppresses tumor cell migration and cardiac angiogenic response in the host. Journal of Biological Chemistry, 287(42), 34866–34882. https://doi.org/10.1074/jbc.M112.374587
Tang, N., Wang, L., Esko, J., Giordano, F. J., Huang, Y., Gerber, H. P., Ferrara, N., & Johnson, R. S. (2004). Loss of HIF-1α in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell, 6(5), 485–495. https://doi.org/10.1016/j.ccr.2004.09.026
Taylor, C. T., & Scholz, C. C. (2022). The effect of HIF on metabolism and immunity. Nature Reviews Nephrology, 18(9), 573–587. https://doi.org/10.1038/s41581-022-00587-8
Tojo, Y., Sekine, H., Hirano, I., Pan, X., Souma, T., Tsujita, T., Kawaguchi, S., Takeda, N., Takeda, K., Fong, G. H., Dan, T., Ichinose, M., Miyata, T., Yamamoto, M., & Suzuki, N. (2015). Hypoxia signaling cascade for erythropoietin production in hepatocytes. Molecular and Cellular Biology, 35(15), 2658–2672. https://doi.org/10.1128/mcb.00161-15
Valdes, A., Pizarro, G., Gonzalez-Montero, J., Rojas, C., & Burotto, M. (2024). Targeting HIF-2α: The role of belzutifan in clear cell renal carcinoma management. Expert Review of Clinical Pharmacology, 18(1-2), 17–27. https://doi.org/10.1080/17512433.2024.2436433
Vaupel, P. (2004). Tumor microenvironmental physiology and its implications for radiation oncology. Seminars in Radiation Oncology, 14(3), 198–206. https://doi.org/10.1016/j.semradonc.2004.04.008
Vignali, P. D. A., DePeaux, K., Watson, M. J., Ye, C., Ford, B. R., Lontos, K., McGaa, N. K., Scharping, N. E., Menk, A. V., Robson, S. C., Poholek, A. C., Rivadeneira, D. B., & Delgoffe, G. M. (2023). Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity. Nature Immunology, 24(2), 267–279. https://doi.org/10.1038/s41590-022-01379-9
Villa-Roel, N., Ryu, K., Gu, L., Fernandez Esmerats, J., Kang, D. W., Kumar, S., & Jo, H. (2022). HIF-1α inhibitor PX-478 reduces atherosclerosis in mice. Atherosclerosis, 344, 20–30. https://doi.org/10.1016/j.atherosclerosis.2022.01.002
Wallace, E. M., Rizzi, J. P., Han, G., Wehn, P. M., Cao, Z., Du, X., Cheng, T., Czerwinski, R. M., Dixon, D. D., Goggin, B. S., Grina, J. A., Halfmann, M. M., Maddie, M. A., Olive, S. R., Schlachter, S. T., Tan, H., Wang, B., Wang, K., Xie, S., … Josey, J. A. (2016). A small-molecule antagonist of HIF-2α is efficacious in preclinical models of renal cell carcinoma. Cancer Research, 76(18), 5491–5500. https://doi.org/10.1158/0008-5472.Can-16-0473
Wang, G. L., & Semenza, G. L. (1993). General involvement of HIF-1α in transcriptional response to hypoxia. Proceedings of the National Academy of Sciences of the United States of America, 90(9), 4304–4308. https://doi.org/10.1073/pnas.90.9.4304
Wang, Q., Yuan, F., Zuo, X., & Li, M. (2025). Breakthroughs and challenges of organoid models for assessing cancer immunotherapy: A cutting-edge tool for advancing personalised treatments. Cell Death Discovery, 11(1). https://doi.org/10.1038/s41420-025-02505-w
Weber, E. W., Parker, K. R., Sotillo, E., Lynn, R. C., Anbunathan, H., Lattin, J., Good, Z., Belk, J. A., Daniel, B., Klysz, D., Malipatlolla, M., Xu, P., Bashti, M., Heitzeneder, S., Labanieh, L., Vandris, P., Majzner, R. G., Qi, Y., Sandor, K., … Mackall, C. L. (2021). Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling. Science, 372(6537). https://doi.org/10.1126/science.aba1786
Wei, P., Kou, W., Riaz, F., Zhang, K., Fu, J., & Pan, F. (2023). Combination therapy of HIF-α inhibitors and Treg depletion strengthen the anti-tumor immunity in mice. European Journal of Immunology, 53(12). https://doi.org/10.1002/eji.202250182
Wenes, M., Shang, M., Di Matteo, M., Goveia, J., Martin-Perez, R., Serneels, J., Prenen, H., Ghesquiere, B., Carmeliet, P., & Mazzone, M. (2016). Macrophage metabolism controls tumor blood vessel morphogenesis and metastasis. Cell Metabolism, 24(5), 701–715. https://doi.org/10.1016/j.cmet.2016.09.008
Werter, I. M., Huijts, C. M., Lougheed, S. M., Hamberg, P., Polee, M. B., Tascilar, M., Los, M., Haanen, J., Helgason, H. H., Verheul, H. M., de Gruijl, T. D., & van der Vliet, H. J. (2019). Metronomic cyclophosphamide attenuates mTOR-mediated expansion of regulatory T cells, but does not impact clinical outcome in patients with metastatic renal cell cancer treated with everolimus. Cancer Immunology, Immunotherapy, 68(5), 787–798. https://doi.org/10.1007/s00262-019-02313-z
Wicks, E. E., & Semenza, G. L. (2022). Hypoxia-inducible factors: Cancer progression and clinical translation. Journal of Clinical Investigation, 132(11). https://doi.org/10.1172/jci159839
Wood, S. M., Gleadle, J. M., Pugh, C. W., Hankinson, O., & Ratcliffe, P. J. (1996). The role of the aryl hydrocarbon receptor nuclear translocator (ARNT) in hypoxic induction of gene expression: Studies in ARNT-deficient cells. Journal of Biological Chemistry, 271(25), 15117–15123. https://doi.org/10.1074/jbc.271.25.15117
Wu, D., & Rastinejad, F. (2017). Structural characterization of mammalian bHLH-PAS transcription factors. Current Opinion in Structural Biology, 43, 1–9. https://doi.org/10.1016/j.sbi.2016.09.011
Wu, H., Zhao, X., Hochrein, S. M., Eckstein, M., Gubert, G. F., Knopper, K., Mansilla, A. M., Oner, A., Doucet-Ladeveze, R., Schmitz, W., Ghesquiere, B., Theurich, S., Dudek, J., Gasteiger, G., Zernecke, A., Kobold, S., Kastenmuller, W., & Vaeth, M. (2023). Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming. Nature Communications, 14(1). https://doi.org/10.1038/s41467-023-42634-3
Wu, Z., Man, S., Sun, R., Li, Z., Wu, Y., & Zuo, D. (2020). Recent advances and challenges of immune checkpoint inhibitors in immunotherapy of non-small cell lung cancer. International Immunopharmacology, 85, 106613. https://doi.org/10.1016/j.intimp.2020.106613
Xie, D., Wang, J., Hu, G., Chen, C., Yang, H., Ritter, J. K., Qu, Y., & Li, N. (2021). Kidney-targeted delivery of prolyl hydroxylase domain protein 2 small interfering RNA with nanoparticles alleviated renal ischemia/reperfusion injury. Journal of Pharmacology and Experimental Therapeutics, 378(3), 235–243. https://doi.org/10.1124/jpet.121.000667
Xu, R., Wang, K., Rizzi, J. P., Huang, H., Grina, J. A., Schlachter, S. T., Wang, B., Wehn, P. M., Yang, H., Dixon, D. D., Czerwinski, R. M., Du, X., Ged, E. L., Han, G., Tan, H., Wong, T., Xie, S., Josey, J. A., & Wallace, E. M. (2019). 3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-zethylsulfonylindan-4-yl] oxy-5-fluorobenzonitrile (PT2977), a HIF-2α inhibitor for the treatment of clear cell renal cell carcinoma. Journal of Medicinal Chemistry, 62(15), 6876–6893. https://doi.org/10.1021/acs.jmedchem.9b00719
Xue, X., Qu, H., & Li, Y. (2022). Stimuli-responsive crosslinked nanomedicine for cancer treatment. Exploration, 2(6). https://doi.org/10.1002/exp.20210134
Xun, Z., Zhou, H., Shen, M., Liu, Y., Sun, C., Du, Y., Jiang, Z., Yang, L., Zhang, Q., Lin, C., Hu, Q., Ye, Y., & Han, L. (2024). Identification of hypoxia-ALCAM (high) macrophage exhausted T cell axis in tumor microenvironment remodeling for immunotherapy resistance. Advanced Science, 11(33). https://doi.org/10.1002/advs.202309885
Yan, Y., Liu, F., Han, L., Zhao, L., Chen, J., Olopade, O. I., He, M., & Wei, M. (2018). HIF-2α promotes conversion to a stem cell phenotype and induces chemoresistance in breast cancer cells by activating Wnt and Notch pathways. Journal of Experimental & Clinical Cancer Research, 37(1). https://doi.org/10.1186/s13046-018-0925-x
Yang, M. H., Wu, M. Z., Chiou, S. H., Chen, P. M., Chang, S. Y., Liu, C. J., Teng, S. C., & Wu, K. J. (2008). Direct regulation of TWIST by HIF-1α promotes metastasis. Nature Cell Biology, 10(3), 295–305. https://doi.org/10.1038/ncb1691
Yuan, X., Ruan, W., Bobrow, B., Carmeliet, P., & Eltzschig, H. K. (2023). Targeting HIFs: Therapeutic opportunities and challenges. Nature Reviews Drug Discovery, 23(3), 175–200. https://doi.org/10.1038/s41573-023-00848-6
Zandberg, D. P., Menk, A. V., Velez, M., Normolle, D., DePeaux, K., Liu, A., Ferris, R. L., & Delgoffe, G. M. (2021). Tumor hypoxia is associated with resistance to PD-1 blockade in squamous cell carcinoma of the head and neck. Journal for ImmunoTherapy of Cancer, 9(5), e002088. https://doi.org/10.1136/jitc-2020-002088
Zhang, H., Brown, R. L., Wei, Y., Zhao, P., Liu, S., Liu, X., Deng, Y., Hu, X., Zhang, J., Gao, X. D., Kang, Y., Mercurio, A. M., Goel, H. L., & Cheng, C. (2019). CD44 splice isoform switching determines breast cancer stem cell state. Genes & Development, 33(3-4), 166–179. https://doi.org/10.1101/gad.319889.118
Zhang, H., Qian, D. Z., Tan, Y. S., Lee, K., Gao, P., Ren, Y. R., Rey, S., Hammers, H., Chang, D., Pili, R., Dang, C. V., Liu, J. O., & Semenza, G. L. (2008). Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth. Proceedings of the National Academy of Sciences of the United States of America, 105(50), 19579–19586. https://doi.org/10.1073/pnas.0809763105
Zhang, L., Cagle, C., Nguyen, D. H., Gomes, G. S., Gromova, B., Csizmadia, E., Karimitar, A., Lee, G. R., Chen, G., Kokkotou, E., Grossberg, L., Jiang, S., Cheifetz, A. S., Kota, S. K., & Longhi, M. S. (2025). Antisense to human CD39 dysregulates immune metabolism in inflammatory bowel disease. Cellular & Molecular Immunology, 22(7), 730–742. https://doi.org/10.1038/s41423-025-01295-6
Zhang, T. Q., Lv, Q. Y., & Jin, W. L. (2024). The cellular-centered view of hypoxia tumor microenvironment: Molecular mechanisms and therapeutic interventions. *Biochimica et Biophysica Acta - Reviews on Cancer, 1879*(5), 189137. https://doi.org/10.1016/j.bbcan.2024.189137
Zhang, Y., Kurupati, R., Liu, L., Zhou, X. Y., Zhang, G., Hudaihed, A., Filisio, F., Giles-Davis, W., Xu, X., Karakousis, G. C., Schuchter, L. M., Xu, W., Amaravadi, R., Xiao, M., Sadek, N., Krepler, C., Herlyn, M., Freeman, G. J., Rabinowitz, J. D., & Ertl, H. C. J. (2017). Enhancing CD8+ T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy. Cancer Cell, 32(3), 377–391.e9. https://doi.org/10.1016/j.ccell.2017.08.004
Zheng, S., Ni, J., Li, Y., Lu, M., Yao, Y., Guo, H., Jiao, M., Jin, T., Zhang, H., Yuan, A., Wang, Z., Yang, Y., Chen, Z., Wu, H., & Hu, W. (2021). 2-Methoxyestradiol synergizes with erlotinib to suppress hepatocellular carcinoma by disrupting the PLAGL2-EGFR-HIF-1/2α signaling loop. Pharmacological Research, 169, 105685. https://doi.org/10.1016/j.phrs.2021.105685
Zheng, X., Qian, Y., Fu, B., Jiao, D., Jiang, Y., Chen, P., Shen, Y., Zhang, H., Sun, R., Tian, Z., & Wei, H. (2019). Mitochondrial fragmentation limits NK cell-based tumor immunosurveillance. Nature Immunology, 20(12), 1656–1667. https://doi.org/10.1038/s41590-019-0511-1
Zhou, M., Xu, L., Hu, J., Chen, W., Hong, J., Wang, M., & Guo, Z. (2025). Metabolic reprogramming through PIM3 inhibition reverses hypoxia-induced CAR-T cell dysfunction in solid tumors. Journal of Translational Medicine, 23(1). https://doi.org/10.1186/s12967-025-07278-5
Zhou, X., Guo, X., Chen, M., Xie, C., & Jiang, J. (2018). HIF-3α promotes metastatic phenotypes in pancreatic cancer by transcriptional regulation of the RhoC-ROCK1 signaling pathway. Molecular Cancer Research, 16(1), 124–134. https://doi.org/10.1158/1541-7786.Mcr-17-0256
