Shirole, N. H. & Kaelin, W. G. von-Hippel Lindau and hypoxia-inducible factor at the center of renal cell carcinoma biology. Hematol. Oncol. Clin. North Am. 37, 809–825 (2023).
Google Scholar
US Food and Drug Administration. FDA approves belzutifan for cancers associated with von Hippel-Lindau disease. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-cancers-associated-von-hippel-lindau-disease (2021).
US Food and Drug Administration. FDA approves belzutifan for advanced renal cell carcinoma. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-advanced-renal-cell-carcinoma (2023).
US Food and Drug Administration. FDA approves belzutifan for pheochromocytoma or paraganglioma. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-pheochromocytoma-or-paraganglioma (2025).
Bao, X. et al. The crosstalk between HIFs and mitochondrial dysfunctions in cancer development. Cell Death Dis. 12, 215 (2021).
Google Scholar
Kaelin, W. G. The VHL tumor suppressor gene: insights into oxygen sensing and cancer. Trans. Am. Clin. Climatol. Assoc. 128, 298–307 (2017).
Google Scholar
Tian, H., McKnight, S. L. & Russell, D. W. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev. 11, 72–82 (1997).
Google Scholar
Erbel, P. J. A., Card, P. B., Karakuzu, O., Bruick, R. K. & Gardner, K. H. Structural basis for PAS domain heterodimerization in the basic helix–loop–helix-PAS transcription factor hypoxia-inducible factor. Proc. Natl Acad. Sci. USA 100, 15504–15509 (2003).
Google Scholar
To, K. K. W. & Huang, L. E. Suppression of hypoxia-inducible factor 1α (HIF-1α) transcriptional activity by the HIF prolyl hydroxylase EGLN1. J. Biol. Chem. 280, 38102–38107 (2005).
Google Scholar
Erez, N. et al. Expression of prolyl-hydroxylase-1 (PHD1/EGLN2) suppresses hypoxia inducible factor-1α activation and inhibits tumor growth. Cancer Res. 63, 8777–8783 (2003).
Google Scholar
Kaelin, W. G. Proline hydroxylation and gene expression. Annu. Rev. Biochem. 74, 115–128 (2005).
Google Scholar
Hon, W.-C. et al. Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL. Nature 417, 975–978 (2002).
Google Scholar
Kaluz, S., Kaluzová, M. & Stanbridge, E. J. Regulation of gene expression by hypoxia: integration of the HIF-transduced hypoxic signal at the hypoxia-responsive element. Clinica Chim. Acta 395, 6–13 (2008).
Google Scholar
Forsythe, J. A. et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol. Cell Biol. 16, 4604–4613 (1996).
Google Scholar
Wang, G. L. & Semenza, G. L. Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia. J. Biol. Chem. 268, 21513–21518 (1993).
Google Scholar
Ebert, B. L., Firth, J. D. & Ratcliffe, P. J. Hypoxia and mitochondrial inhibitors regulate expression of glucose transporter-1 via distinct Cis-acting sequences. J. Biol. Chem. 270, 29083–29089 (1995).
Google Scholar
Semenza, G. L., Roth, P. H., Fang, H. M. & Wang, G. L. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J. Biol. Chem. 269, 23757–23763 (1994).
Google Scholar
Carroll, V. A. & Ashcroft, M. Role of hypoxia-inducible factor (HIF)-1α versus HIF-2α in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway. Cancer Res. 66, 6264–6270 (2006).
Google Scholar
Piret, J.-P. et al. Hypoxia-inducible factor-1-dependent overexpression of myeloid cell factor-1 protects hypoxic cells against tert-butyl hydroperoxide-induced apoptosis. J. Biol. Chem. 280, 9336–9344 (2005).
Google Scholar
Bindra, R. S., Vasselli, J. R., Stearman, R., Linehan, W. M. & Klausner, R. D. VHL-mediated hypoxia regulation of cyclin D1 in renal carcinoma cells. Cancer Res. 62, 3014–3019 (2002).
Google Scholar
Bratslavsky, G., Sudarshan, S., Neckers, L. & Linehan, W. M. Pseudohypoxic pathways in renal cell carcinoma. Clin. Cancer Res. 13, 4667–4671 (2007).
Google Scholar
Friedrich, C. A. Von Hippel-Lindau syndrome. Cancer 86, 2478–2482 (1999).
Google Scholar
Banks, R. E. et al. Genetic and epigenetic analysis of von Hippel-Lindau (VHL) gene alterations and relationship with clinical variables in sporadic renal cancer. Cancer Res. 66, 2000–2011 (2006).
Google Scholar
Creighton, C. J. et al. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43–49 (2013).
Google Scholar
Krieg, M. et al. Up-regulation of hypoxia-inducible factors HIF-1α and HIF-2α under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function. Oncogene 19, 5435–5443 (2000).
Google Scholar
Kaelin, W. G. Molecular basis of the VHL hereditary cancer syndrome. Nat. Rev. Cancer 2, 673–682 (2002).
Google Scholar
Iliopoulos, O., Levy, A. P., Jiang, C., Kaelin, W. G. & Goldberg, M. A. Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc. Natl Acad. Sci. USA 93, 10595–10599 (1996).
Google Scholar
Selak, M. A. et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase. Cancer Cell 7, 77–85 (2005).
Google Scholar
Pollard, P. J. et al. Targeted inactivation of Fh1 causes proliferative renal cyst development and activation of the hypoxia pathway. Cancer Cell 11, 311–319 (2007).
Google Scholar
Cascón, A. et al. Whole-exome sequencing identifies MDH2 as a new familial paraganglioma gene. J. Natl Cancer Inst. 107, djv053 (2015).
Google Scholar
Kaelin, W. G. The von Hippel–Lindau protein, HIF hydroxylation, and oxygen sensing. Biochem. Biophys. Res. Commun. 338, 627–638 (2005).
Google Scholar
Neumann, H. P. H., Young, W. F. & Eng, C. Pheochromocytoma and paraganglioma. N. Engl. J. Med. 381, 552–565 (2019).
Google Scholar
Pollard, P. J. et al. Accumulation of krebs cycle intermediates and over-expression of HIF1α in tumours which result from germline FH and SDH mutations. Hum. Mol. Genet. 14, 2231–2239 (2005).
Google Scholar
Menko, F. H. et al. Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment. Fam. Cancer 13, 637–644 (2014).
Google Scholar
Sudarshan, S., Linehan, W. M. & Neckers, L. HIF and fumarate hydratase in renal cancer. Br. J. Cancer 96, 403–407 (2007).
Google Scholar
Isaacs, J. S. et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 8, 143–153 (2005).
Google Scholar
Adam, J. et al. Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer Cell 20, 524–537 (2011).
Google Scholar
Pan, Y. et al. Multiple factors affecting cellular redox status and energy metabolism modulate hypoxia-inducible factor prolyl hydroxylase activity in vivo and in vitro. Mol. Cell Biol. 27, 912–925 (2007).
Google Scholar
Ban, H. S. et al. A novel malate dehydrogenase 2 inhibitor suppresses hypoxia-inducible factor-1 by regulating mitochondrial respiration. PLoS ONE 11, e0162568 (2016).
Google Scholar
Delamare, M. et al. Characterization of genetic variants in the EGLN1/PHD2 gene identified in a European collection of patients with erythrocytosis. Haematologica 108, 3068–3085 (2023).
Google Scholar
Ladroue, C. et al. PHD2 mutation and congenital erythrocytosis with paraganglioma. N. Engl. J. Med. 359, 2685–2692 (2008).
Google Scholar
Zhuang, Z. et al. Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. N. Engl. J. Med. 367, 922–930 (2012).
Google Scholar
Rosenblum, J. S., Wang, H., Nazari, M. A., Zhuang, Z. & Pacak, K. Pacak-Zhuang syndrome: a model providing new insights into tumor syndromes. Endocr. Relat. Cancer 30, e230050 (2023).
Google Scholar
Cole, Y. et al. Expanding the clinical tumor phenotype of the EPAS1-asssociated tumor syndrome. J. Clin. Endocrinol. Metab. (2026).
Wang, J. J. et al. ELOC-mutated renal cell carcinoma is a rare indolent tumor with distinctive genomic characteristics. Mod. Pathol. 38, 100777 (2025).
Google Scholar
Vocke, C. D. et al. Multigenerational VHL family characterized by pathogenic germline ELOC variant: response to belzutifan. Urol. Oncol. 44, 120.e21–120.e27 (2026).
Google Scholar
Wiesener, M. S. et al. Widespread hypoxia-inducible expression of HIF-2α in distinct cell populations of different organs. FASEB J. 17, 271–273 (2003).
Google Scholar
Rosenberger, C. et al. Expression of hypoxia-inducible factor-1α and -2α in hypoxic and ischemic rat kidneys. J. Am. Soc. Nephrol. 13, 1721 (2002).
Google Scholar
Prange-Barczynska, M. et al. Hif-2α programs oxygen chemosensitivity in chromaffin cells. J. Clin. Invest. 134, e174661 (2024).
Google Scholar
Wiesener, M. S. et al. Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1α. Blood 92, 2260–2268 (1998).
Google Scholar
Hu, C.-J., Wang, L.-Y., Chodosh, L. A., Keith, B. & Simon, M. C. Differential roles of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α in hypoxic gene regulation. Mol. Cell Biol. 23, 9361–9374 (2003).
Google Scholar
Gordan, J. D., Thompson, C. B. & Simon, M. C. HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell 12, 108–113 (2007).
Google Scholar
Koshiji, M. et al. HIF-1α induces cell cycle arrest by functionally counteracting Myc. EMBO J. 23, 1949–1956 (2004).
Google Scholar
Baba, M. et al. Loss of von Hippel-Lindau protein causes cell density dependent deregulation of CyclinD1 expression through hypoxia-inducible factor. Oncogene 22, 2728–2738 (2003).
Google Scholar
Gordan, J. D., Bertovrt, J. A., Hu, C.-J., Diehl, J. A. & Simon, M. C. HIF-2α promotes hypoxic cell proliferation by enhancing c-Myc transcriptional activity. Cancer Cell 11, 335–347 (2007).
Google Scholar
Smythies, J. A. et al. Inherent DNA-binding specificities of the HIF-1α and HIF-2α transcription factors in chromatin. EMBO Rep. 20, e46401 (2019).
Google Scholar
Hu, C.-J., Sataur, A., Wang, L., Chen, H. & Simon, M. C. The N-terminal transactivation domain confers target gene specificity of hypoxia-inducible factors HIF-1α and HIF-2α. Mol. Biol. Cell 18, 4528–4542 (2007).
Google Scholar
Koh, M. Y. & Powis, G. Passing the baton: the HIF switch. Trends Biochem. Sci. 37, 364–372 (2012).
Google Scholar
Ravenna, L., Salvatori, L. & Russo, M. A. HIF3α: the little we know. FEBS J. 283, 993–1003 (2016).
Google Scholar
Davis, L. et al. Targeting HIF-2α in the tumor microenvironment: redefining the role of HIF-2α for solid cancer therapy. Cancers 14, 1259 (2022).
Google Scholar
Vaupel, P. & Mayer, A. Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev. 26, 225–239 (2007).
Google Scholar
Moreno Roig, E. et al. Prognostic role of hypoxia-inducible factor-2α tumor cell expression in cancer patients: a meta-analysis. Front. Oncol. 8, 224 (2018).
Google Scholar
Lu, X. & Kang, Y. Hypoxia and hypoxia-inducible factors: master regulators of metastasis. Clin. Cancer Res. 16, 5928–5935 (2010).
Google Scholar
Hanna, S. C. et al. HIF1α and HIF2α independently activate SRC to promote melanoma metastases. J. Clin. Invest. 123, 2078–2093 (2013).
Google Scholar
Branco-Price, C. et al. Endothelial cell HIF-1α and HIF-2α differentially regulate metastatic success. Cancer Cell 21, 52–65 (2012).
Google Scholar
Kim, W. Y. et al. HIF2α cooperates with RAS to promote lung tumorigenesis in mice. J. Clin. Invest. 119, 3182–3182 (2009).
Google Scholar
Franovic, A., Holterman, C. E., Payette, J. & Lee, S. Human cancers converge at the HIF-2α oncogenic axis. Proc. Natl Acad. Sci. USA 106, 21306–21311 (2009).
Google Scholar
Linehan, W. M., Srinivasan, R. & Schmidt, L. S. The genetic basis of kidney cancer: a metabolic disease. Nat. Rev. Urol. 7, 277–285 (2010).
Google Scholar
Kondo, K., Kim, W. Y., Lechpammer, M. & Kaelin, W. G. Inhibition of HIF2α is sufficient to suppress pVHL-defective tumor growth. PLoS Biol. 1, E83 (2003).
Google Scholar
Maynard, M. A. et al. Dominant-negative HIF-3α4 suppresses VHL-null renal cell carcinoma progression. Cell Cycle 6, 2810–2816 (2007).
Google Scholar
Zimmer, M. et al. Small-molecule inhibitors of HIF-2a translation link its 5’UTR iron-responsive element to oxygen sensing. Mol. Cell 32, 838–848 (2008).
Google Scholar
Yan, C. & Higgins, P. J. Drugging the undruggable: transcription therapy for cancer. Biochim. Biophys. Acta Rev. Cancer 1835, 76–85 (2013).
Google Scholar
Rogers, J. L. et al. Development of inhibitors of the PAS-B domain of the HIF-2α transcription factor. J. Med. Chem. 56, 1739–1747 (2013).
Google Scholar
Scheuermann, T. H. et al. Artificial ligand binding within the HIF2α PAS-B domain of the HIF2 transcription factor. Proc. Natl Acad. Sci. USA 106, 450–455 (2009).
Google Scholar
Scheuermann, T. H. et al. Allosteric inhibition of hypoxia inducible factor-2 with small molecules. Nat. Chem. Biol. 9, 271–276 (2013).
Google Scholar
Wallace, E. M. et al. A small-molecule antagonist of HIF2α is efficacious in preclinical models of renal cell carcinoma. Cancer Res. 76, 5491–5500 (2016).
Google Scholar
Courtney, K. D. et al. Phase I dose-escalation trial of PT2385, a first-in-class hypoxia-inducible factor-2α antagonist in patients with previously treated advanced clear cell renal cell carcinoma. J. Clin. Oncol. 36, 867–874 (2018).
Google Scholar
Xu, R. et al. 3-[(1S,2S,3R)-2,3-difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977), a hypoxia-inducible factor 2α (HIF-2α) inhibitor for the treatment of clear cell renal cell carcinoma. J. Med. Chem. 62, 6876–6893 (2019).
Google Scholar
Chen, W. et al. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature 539, 112–117 (2016).
Google Scholar
Cho, H. et al. On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models. Nature 539, 107–111 (2016).
Google Scholar
Merck buys maker of HIF2α inhibitor. Cancer Discov. 9, OF4 (2019).
Papadopoulos, K. P., Jonasch, E., Zojwalla, N. J., Wang, K. & Bauer, T. M. A first-in-human phase 1 dose-escalation trial of the oral HIF-2a inhibitor PT2977 in patients with advanced solid tumors. J. Clin. Oncol. 36, 2508 (2018).
Choueiri, T. K. et al. Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. Nat. Med. 27, 802–805 (2021).
Google Scholar
Choueiri, T. K. et al. Phase I/II study of the oral HIF-2 α inhibitor MK-6482 in patients with advanced clear cell renal cell carcinoma (RCC). J. Clin. Oncol. 38, 611 (2020).
Jonasch, E. et al. Belzutifan for renal cell carcinoma in von Hippel–Lindau disease. N. Engl. J. Med. 385, 2036–2046 (2021).
Google Scholar
Narayan, V. et al. Hypoxia-inducible factor-2α (HIF-2α) inhibitor belzutifan in von Hippel-Lindau (VHL) disease–associated neoplasms: 5-year follow-up of the phase 2 LITESPARK-004 study. J. Clin. Oncol. 43, 4507 (2025).
Iliopoulos, O. et al. Belzutifan for patients with von Hippel-Lindau disease-associated CNS haemangioblastomas (LITESPARK-004): a multicentre, single-arm, phase 2 study. Lancet Oncol. 25, 1325–1336 (2024).
Google Scholar
Else, T. et al. Belzutifan for von Hippel–Lindau disease: pancreatic lesion population of the phase 2 LITESPARK-004 study. Clin. Cancer Res. 30, 1750–1757 (2024).
Google Scholar
Gong, K. et al. Phase 2 trial of belzutifan in participants from China and Japan with von hippel-lindau disease-associated tumors: results from LITESPARK-015 cohort B1. J. Clin. Oncol. 44, 494 (2026).
Choueiri, T. K. et al. Belzutifan versus everolimus for advanced renal-cell carcinoma. N. Engl. J. Med. 391, 710–721 (2024).
Google Scholar
Agarwal, N. et al. Randomized phase II dose comparison LITESPARK-013 study of belzutifan in patients with advanced clear cell renal cell carcinoma. Ann. Oncol. 35, 1148–1156 (2024).
Google Scholar
Mata, G. et al. Stereodivergent synthesis of the vicinal difluorinated tetralin of casdatifan enabled by Ru-catalyzed transfer hydrogenation. Org. Lett. 27, 833–839 (2025).
Google Scholar
Ghasemi, M. et al. Pharmacokinetics, pharmacodynamics and safety of casdatifan, a novel hypoxia-inducible factor-2α inhibitor, in healthy participants. Br. J. Clin. Pharmacol. 91, 3366–3377 (2025).
Google Scholar
Choueiri, T. K. et al. Activity and biomarker analyses with casdatifan (cas), a next-generation HIF-2α inhibitor, in refractory clear cell renal cell carcinoma (ccRCC): results from ARC-20. J. Clin. Oncol. 44, 493 (2026).
Pal, S. K. et al. A phase I dose-escalation study of the HIF-2 alpha inhibitor DFF332 in patients with advanced clear-cell renal cell carcinoma. Clin. Cancer Res. 31, 1847–1855 (2025).
Google Scholar
Seymour, C. NKT2152 data reinforce the importance of HIF2α inhibition in advanced clear cell RCC. OncLive https://www.onclive.com/view/nkt2152-data-reinforce-the-importance-of-hif2-inhibition-in-advanced-clear-cell-rcc (2026).
Jonasch, E. et al. 1690O NKT2152, a novel oral HIF-2α inhibitor, in participants (pts) with previously treated advanced clear cell renal carcinoma (accRCC): preliminary results of a phase I/II study. Ann. Oncol. 35, S1011–S1012 (2024).
Wang, P. et al. Abstract 494: BPI-452080: a potent and selective HIF-2α inhibitor for the treatment of clear cell renal cell carcinoma, von Hippel-Lindau disease, and other solid tumors. Cancer Res. 83, 494 (2023).
Green, Y. S., dos Santos, M. F., Ciofi-Baffoni, S., Liu, X. & Koh, M. Y. Abstract 2096: a novel, orally available ferroptosis inducer targeting Fe-S assembly with significant in vivo anti-tumor efficacy. Cancer Res. 84, 2096 (2024).
Wang, Z., Kong, D. & Wei, W. The role of ferroptosis in renal cell carcinoma: molecular mechanisms and therapeutic implications. J. Mol. Med. 104, 22 (2026).
Google Scholar
Wong, S. C. et al. HIF2α-targeted RNAi therapeutic inhibits clear cell renal cell carcinoma. Mol. Cancer Therapeut. 17, 140–149 (2018).
Google Scholar
Wong, S. C. et al. Abstract 4775: Optimizing the potency and dosing design for ARO-HIF2: an RNAi therapeutic for clear cell renal cell carcinoma. Cancer Res. 79, 4775 (2019).
Ma, Y. et al. HIF2 inactivation and tumor suppression with a tumor-directed RNA-silencing drug in mice and humans. Clin. Cancer Res. 28, 5405–5418 (2022).
Google Scholar
Brugarolas, J. et al. A first-in-human phase 1 study of a tumor-directed RNA-interference drug against HIF2α in patients with advanced clear cell renal cell carcinoma. Clin. Cancer Res. 30, 2402–2411 (2024).
Google Scholar
Choueiri, T. K. et al. Updated results from the phase 2 LITESPARK-003 study of belzutifan plus cabozantinib in patients with advanced clear cell renal cell carcinoma (ccRCC). J. Clin. Oncol. 43, 549 (2025).
Albiges, L. et al. KEYMAKER-U03 substudy 03B: novel investigative regimens for previously treated advanced clear cell renal cell carcinoma (ccRCC). J. Clin. Oncol. 44, 505 (2026).
Motzer, R. J. et al. LITESPARK-011: belzutifan plus lenvatinib vs cabozantinib in advanced renal cell carcinoma after anti-PD-1/PD-L1 therapy. Future Oncol. 19, 113–121 (2023).
Google Scholar
Motzer, R. J. et al. Belzutifan (bel) plus lenvatinib (lenva) versus cabozantinib (cabo) for advanced renal cell carcinoma (RCC) after anti–PD-(L)1 therapy: Open-label phase 3 LITESPARK-011 study. J. Clin. Oncol. 44, LBA417 (2026).
Sheng, X. et al. Belzutifan plus lenvatinib (len) for Chinese patients (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC): preliminary results of cohort 1 of the phase 1 LITESPARK-010 study. J. Clin. Oncol. 42, 4537 (2024).
Sheng, X. et al. 2615P Belzutifan plus lenvatinib for Chinese participants (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC): updated results of cohort 1 of the LITESPARK-010 study. Ann. Oncol. 36, S1313 (2025).
Suarez, C. et al. Novel pembrolizumab-based treatments as first-line therapy in advanced clear cell renal cell carcinoma: Substudy 03A of the open-label, umbrella platform, phase I/II KEYMAKER-U03 trial. Ann. Oncol. 37, 229–240 (2025).
Google Scholar
Motzer, R. J. et al. Lenvatinib plus pembrolizumab versus sunitinib in first-line treatment of advanced renal cell carcinoma: final prespecified overall survival analysis of clear, a phase III study. J. Clin. Oncol. 42, 1222–1228 (2024).
Google Scholar
Motzer, R. J. et al. Final analysis of nivolumab plus cabozantinib for advanced renal cell carcinoma from the randomized phase III CheckMate 9ER trial. Ann. Oncol. 37, 33–43 (2026).
Google Scholar
Rini, B. I. et al. Pembrolizumab plus axitinib versus sunitinib for advanced clear cell renal cell carcinoma: 5-year survival and biomarker analyses of the phase 3 KEYNOTE-426 trial. Nat. Med. 31, 3475–3484 (2025).
Google Scholar
Choueiri, T. K. et al. LITESPARK-012: pembrolizumab plus lenvatinib with or without belzutifan or quavonlimab for advanced renal cell carcinoma. Future Oncol. 19, 2631–2640 (2023).
Google Scholar
Choueiri, T. K. et al. Combination casdatifan plus cabozantinib expansion cohort of phase 1 ARC-20 study in previously treated patients with clear cell renal cell carcinoma. J. Clin. Oncol. 43, 4506 (2025).
ASCO 2025: Combination casdatifan plus cabozantinib expansion cohort of phase 1 ARC-20 study in previously treated patients with clear cell renal cell carcinoma. UroToday https://www.urotoday.com/conference-highlights/asco-2025/asco-2025-kidney-cancer/160907-asco-2025-combination-casdatifan-plus-cabozantinib-expansion-cohort-of-phase-1-arc-20-study-in-previously-treated-patients-with-clear-cell-renal-cell-carcinoma.html (2025).
Han, G. et al. Abstract 4022: PT2385, a novel HIF-2α antagonist, combines with checkpoint inhibitor antibodies to inhibit tumor growth in preclinical models by modulating myeloid cells and enhancing T cell infiltration. Cancer Res. 76, 4022 (2016).
Schweickert, P. G. et al. Casdatifan (AB521) is a novel and potent allosteric small molecule inhibitor of protumourigenic HIF-2α dependent transcription. Br. J. Pharmacol. 182, 4147–4167 (2025).
Google Scholar
Rini, B. I. et al. Results from a phase I expansion cohort of the first-in-class oral HIF-2α inhibitor PT2385 in combination with nivolumab in patients with previously treated advanced RCC. J. Clin. Oncol. 37, 558 (2019).
Choueiri, T. K. et al. Overall survival with adjuvant pembrolizumab in renal-cell carcinoma. N. Engl. J. Med. 390, 1359–1371 (2024).
Google Scholar
Choueiri, T. K. et al. LITESPARK-022: a phase 3 study of pembrolizumab + belzutifan as adjuvant treatment of clear cell renal cell carcinoma (ccRCC). J. Clin. Oncol. 40, TPS4602 (2022).
Choueiri, T. K. et al. Adjuvant pembrolizumab plus belzutifan versus pembrolizumab for clear cell renal cell carcinoma (ccRCC): the randomized phase 3 LITESPARK-022 study. J. Clin. Oncol. 44, LBA418 (2026).
Jiang, Q. et al. HIF regulates multiple translated endogenous retroviruses: implications for cancer immunotherapy. Cell 188, 1807–1827.e34 (2025).
Google Scholar
Clark, D. J. et al. Integrated proteogenomic characterization of clear cell renal cell carcinoma. Cell 179, 964–983.e31 (2019).
Google Scholar
Hedberg, Y., Ljungberg, B., Roos, G. & Landberg, G. Retinoblastoma protein in human renal cell carcinoma in relation to alterations in G1/S regulatory proteins. Int. J. Cancer 109, 189–193 (2004).
Google Scholar
Schödel, J. et al. Common genetic variants at the 11q13.3 renal cancer susceptibility locus influence binding of HIF to an enhancer of cyclin D1 expression. Nat. Genet. 44, 420–425 (2012).
Google Scholar
Nicholson, H. E. et al. HIF-independent synthetic lethality between CDK4/6 inhibition and VHL loss across species. Sci. Signal. 12, eaay0482 (2019).
Google Scholar
McGregor, B. A. et al. CDK4/6 inhibition with abemaciclib in patients with previously treated advanced renal cell carcinoma. Clin. Genitourin. Cancer 23, 102318 (2025).
Google Scholar
McDermott, D. F. et al. LITESPARK-024: a randomized phase 1/2 study of belzutifan with or without palbociclib in patients with advanced renal cell carcinoma. J. Clin. Oncol. 41, TPS747 (2023).
McDermott, D. F. et al. Ascending dose escalation of belzutifan plus palbociclib for previously treated advanced clear cell renal cell carcinoma (ccRCC): phase 1/2 LITESPARK-024 study part 1. J. Clin. Oncol. 44, 423 (2026).
Chikashige, Y. et al. Gcn2 eIF2α kinase mediates combinatorial translational regulation through nucleotide motifs and uORFs in target mRNAs. Nucleic Acids Res. 48, 8977–8992 (2020).
Google Scholar
Stokes, M. E. et al. Abstract 4615: HC-7366, a potent GCN2 activator, complements belzutifan, a HIF-2α antagonist, by providing combination benefit in belzutifan-sensitive models and monotherapy activity in belzutifan-resistant models. Cancer Res. 84, 4615 (2024).
Shah, N. J. et al. A phase 1b, open-label, safety, tolerability, and efficacy study of HC-7366 in combination with belzutifan in patients with advanced or metastatic renal cell carcinoma (NCT06234605). J. Clin. Oncol. 43, TPS609 (2025).
Rankin, E. B. et al. Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J. Clin. Invest. 117, 1068–1077 (2007).
Google Scholar
Haase, V. H., Tanaka, T. & Koury, M. J. Hypoxia-inducible factor activators: a novel class of oral drugs for the treatment of anemia of chronic kidney disease. Hematology 2024, 409–418 (2024).
Google Scholar
Choueiri, T. K. et al. 39 Safety profile of belzutifan monotherapy in patients with renal cell carcinoma: a pooled analysis of 4 clinical trials. Oncologist 29, S2–S3 (2024).
Google Scholar
US Food and Drug Administration. WELIREG (belzutifan) tablets, for oral use. FDA https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215383s000lbl.pdf (2024).
Siqueira Do Amaral, P. et al. Long-term safety of belzutifan in von Hippel-Lindau syndrome: a single-center experience. J. Clin. Oncol. 43, 10605 (2025).
Srinivasan, R. et al. Belzutifan for von Hippel-Lindau disease-associated renal cell carcinoma and other neoplasms (LITESPARK-004): 50 months follow-up from a single-arm, phase 2 study. Lancet Oncol. 26, 571–582 (2025).
Google Scholar
Hodson, E. J. et al. Regulation of ventilatory sensitivity and carotid body proliferation in hypoxia by the PHD2/HIF-2 pathway. J. Physiol. 594, 1179–1195 (2016).
Google Scholar
Cheng, X. et al. Marked and rapid effects of pharmacological HIF-2α antagonism on hypoxic ventilatory control. J. Clin. Invest. 130, 2237–2251 (2020).
Google Scholar
Poliakova, L. A. Familial erythrocytosis among the residents of the Chuvash ASSR [Russian]. Probl. Gematol. Pereliv. Krovi 19, 30–33 (1974).
Google Scholar
Hickey, M. M. et al. The von Hippel–Lindau Chuvash mutation promotes pulmonary hypertension and fibrosis in mice. J. Clin. Invest. 120, 827–839 (2010).
Google Scholar
Ghosh, M. C. et al. Therapeutic inhibition of HIF-2α reverses polycythemia and pulmonary hypertension in murine models of human diseases. Blood 137, 2509–2519 (2021).
Google Scholar
Dai, Z. et al. Therapeutic targeting of vascular remodeling and right heart failure in pulmonary arterial hypertension with a HIF-2α inhibitor. Am. J. Respir. Crit. Care Med. 198, 1423–1434 (2018).
Google Scholar
Alkaissi, H., Pacak, K. & Rosenblum, J. Belzutifan versus everolimus for advanced renal-cell carcinoma. N. Engl. J. Med. 391, 2061–2062 (2024).
Google Scholar
McFarland, T. R. et al. Incidence of symptomatic hypoxia in a high-altitude cohort of patients with renal cell carcinoma (RCC) treated with belzutifan. J. Clin. Oncol. 44, 488 (2026).
Roberti de Oliveira, G. et al. Abstract A003: baseline levels of HIF2 target proteins and response to the HIF2α inhibitor NKT2152 in patients with metastatic clear cell renal cell carcinoma. Mol. Cancer Ther. 24, A003 (2025).
Agarwal, N. et al. Biomarker analysis from the phase 2 LITESPARK-013 study of 2 different belzutifan (bel) doses in participants (pts) with advanced clear cell renal cell carcinoma (ccRCC). J. Clin. Oncol. 44, 545 (2026).
Guan, Y. et al. Abstract A023: erythropoietin (EPO) is a pharmacodynamic biomarker for systemic HIF-2α inhibition that correlates with the clinical activity of casdatifan. Mol. Cancer Ther. 24, A023 (2025).
Chen, Y.-W. et al. Genomic and clinical correlates of belzutifan treatment in renal cell carcinoma (RCC): a retrospective analysis of 240 RCC patients. J. Clin. Oncol. 44, 528 (2026).
Mathews, P., Gruber, J., Schoen, M. W., Pachynski, R. K. & Knoche, E. M. Real-world outcomes of clear-cell renal cell carcinoma (ccRCC) patients treated with belzutifan stratified by von Hippel-Lindau (VHL) status. J. Clin. Oncol. 44, 475 (2026).
Wu, D., Potluri, N., Lu, J., Kim, Y. & Rastinejad, F. Structural integration in hypoxia-inducible factors. Nature 524, 303–308 (2015).
Google Scholar
Wu, D. et al. Bidirectional modulation of HIF-2 activity through chemical ligands. Nat. Chem. Biol. 15, 367–376 (2019).
Google Scholar
Natarajan, V., Satalkar, V., Gumbart, J. C. & Torres, M. Molecular dynamics reveals altered interactions between belzutifan and HIF-2 with natural variant G323E or proximal phosphorylation at T324. ACS Omega 9, 37843–37855 (2024).
Google Scholar
Courtney, K. D. et al. HIF-2 complex dissociation, target inhibition, and acquired resistance with PT2385, a first-in-class HIF-2 inhibitor, in patients with clear cell renal cell carcinoma. Clin. Cancer Res. 26, 793–803 (2020).
Google Scholar
Stransky, L. A. et al. Sensitivity of VHL mutant kidney cancers to HIF2 inhibitors does not require an intact p53 pathway. Proc. Natl Acad. Sci. USA 119, e2120403119 (2022).
Google Scholar
Basin, M. et al. MP04-12 pharmacological inhibition of the molecular chaperone HSP70 overcomes belzutifan resistance in CCRCC. J. Urol. 209, e37 (2023).
Liu, R. et al. FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to the HIF2α blockade by facilitating LDHA phosphorylation. Cell Death Dis. 15, 64 (2024).
Google Scholar
Zhao, J., Du, F., Shen, G., Zheng, F. & Xu, B. The role of hypoxia-inducible factor-2 in digestive system cancers. Cell Death Dis. 6, e1600 (2015).
Google Scholar
Bai, J. et al. HIF-2α regulates CD44 to promote cancer stem cell activation in triple-negative breast cancer via PI3K/AKT/mTOR signaling. World J. Stem Cell 12, 87–99 (2020).
Singhal, R. et al. HIF-2α activation potentiates oxidative cell death in colorectal cancers by increasing cellular iron. J. Clin. Invest. 131, e143691 (2021).
Google Scholar
Pavlakis, D. et al. Hypoxia-inducible factor 2a expression is positively correlated with Gleason score in prostate cancer. Technol. Cancer Res. Treat. 20, 1533033821990010 (2021).
Google Scholar
Kamihara, J. et al. Belzutifan, a potent HIF2α inhibitor, in the Pacak–Zhuang syndrome. N. Engl. J. Med. 385, 2059–2065 (2021).
Google Scholar
Alkaissi, H. et al. Rapid cardiovascular response to belzutifan in HIF2A-mediated paraganglioma. N. Engl. J. Med. 391, 1552–1555 (2024).
Google Scholar
Jimenez, C. et al. Belzutifan for advanced pheochromocytoma or paraganglioma. N. Engl. J. Med. 393, 2012–2022 (2025).
Google Scholar
Alkaissi, H. et al. Belzutifan for HIF2A-related pheochromocytoma and paraganglioma: a retrospective study of real-world data. Endocr. Pract. 32, 201–205 (2026).
Google Scholar
Rojas, C. et al. Phase 2 study of pembrolizumab plus lenvatinib and belzutifan in patients with metastatic esophageal squamous cell carcinoma. J. Clin. Oncol. 42, TPS425 (2024).
Alam, M. W. et al. HIF2α contributes to antiestrogen resistance via positive bilateral crosstalk with EGFR in breast cancer cells. Oncotarget 7, 11238–11250 (2016).
Google Scholar
Fu, X. et al. FOXA1 upregulation promotes enhancer and transcriptional reprogramming in endocrine-resistant breast cancer. Proc. Natl Acad. Sci. USA 116, 26823–26834 (2019).
Google Scholar
Lim, B., Jia, L., Sudheendra, P. K. & Hirshfield, K. M. LITESPARK-029: a phase 2, randomized, open-label study of belzutifan plus fulvestrant in participants with estrogen receptor–positive, HER2-negative unresectable locally advanced or metastatic breast cancer after progression on previous endocrine therapy. J. Clin. Oncol. 43, TPS1124 (2025).
Renfrow, J. J. et al. Hypoxia-inducible factor 2α: a novel target in gliomas. Future Med. Chem. 10, 2227–2236 (2018).
Google Scholar
Renfrow, J. J. et al. Attenuating hypoxia driven malignant behavior in glioblastoma with a novel hypoxia-inducible factor 2 alpha inhibitor. Sci. Rep. 10, 15195 (2020).
Google Scholar
Espinoza, F. I. et al. Targeting HIF-2α in glioblastoma reshapes the immune infiltrate and enhances response to immune checkpoint blockade. Cell Mol. Life Sci. 82, 119 (2025).
Google Scholar
Strowd, R. et al. Activity of a first-in-class oral HIF2-alpha inhibitor, PT2385, in patients with first recurrence of glioblastoma. J. Neurooncol 165, 101–112 (2023).
Google Scholar
Strowd, R. E. et al. Phase 1 LITESPARK-001 study of belzutifan in advanced solid tumors: results of the glioblastoma cohort. J. Clin. Oncol. 42, 2054 (2024).
Cameron, S. et al. Chronic hypoxia favours adoption to a castration-resistant cell state in prostate cancer. Oncogene 42, 1693–1703 (2023).
Google Scholar
Yu, E. Y. et al. Phase 1b/2 study of pembrolizumab plus belzutifan and belzutifan alone in patients with docetaxel-treated metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-365 cohort J. J. Clin. Oncol. 42, TPS250 (2024).
Lee, J. S. & Ruppin, E. Multiomics prediction of response rates to therapies to inhibit programmed cell death 1 and programmed cell death 1 ligand 1. JAMA Oncol. 5, 1614–1618 (2019).
Google Scholar
Tjomsland, V. et al. The desmoplastic stroma plays an essential role in the accumulation and modulation of infiltrated immune cells in pancreatic adenocarcinoma. Clin. Dev. Immunol. 2011, 212810 (2011).
Google Scholar
Garcia Garcia, C. J. et al. Stromal HIF2 regulates immune suppression in the pancreatic cancer microenvironment. Gastroenterology 162, 2018–2031 (2022).
Google Scholar
Capdevila, J. et al. 1710MO Belzutifan for advanced pancreatic neuroendocrine tumors (panNETs): results from cohort A2 of the phase II LITESPARK-015 study. Ann. Oncol. 36, S1008–S1009 (2025).
Kim, H. L. et al. Paraneoplastic signs and symptoms of renal cell carcinoma: implications for prognosis. J. Urol. 170, 1742–1746 (2003).
Google Scholar
Sun, R. et al. Prognostic impact of paraneoplastic syndromes on patients with non-metastatic renal cell carcinoma undergoing surgery: results from Canadian Kidney Cancer Information System. Can. Urol. Assoc. J. 15, 132–137 (2021).
Google Scholar
Manisterski, M., Golan, M., Amir, S., Weisman, Y. & Mabjeesh, N. Hypoxia induces PTHrP gene transcription in human cancer cells through the HIF-2α. Cell Cycle 9, 3747–3753 (2010).
Mal, A. et al. HIF-2-dependent regulation of PTHrP and paraneoplastic hypercalcemia in aggressive clear-cell renal cell carcinoma. Cancer Discov. 15, 2485–2504 (2025).
Google Scholar
Abu-Remaileh, M. et al. Targeting of HIF2-driven cachexia in kidney cancer. Nat. Med. 32, 245–257 (2026).
Google Scholar
