Hypoxia-inducible factor 2α (HIF2α; also known as endothelial PAS domain-containing protein 1) had long been considered an undruggable transcription factor until the discovery of an allosteric pocket within its PAS-B domain enabled the development of selective small-molecule antagonists. Belzutifan, the first-in-class HIF2α inhibitor, has since demonstrated substantial efficacy in patients with von Hippel–Lindau (VHL) disease-associated tumours, sporadic clear-cell renal cell carcinoma (ccRCC), and pheochromocytoma or paraganglioma, thereby validating HIF2α as a therapeutic target in patients with cancer.
In this Review, we summarize the biology of the VHL–HIF signalling pathway, the structural basis for HIF2α druggability and the clinical milestones leading to the multiple regulatory approvals of belzutifan. We also highlight emerging data on other small-molecule inhibitors, RNA interference approaches and indirect modulators that have the potential to expand the scope of HIF pathway suppression.
Combination strategies offer opportunities to enhance efficacy and overcome resistance; however, key challenges remain, including the identification of predictive biomarkers, mechanisms of primary and acquired resistance, and optimal management approaches for on-target toxicities such as anaemia and hypoxia.
The discovery of a ligand-accessible allosteric pocket within the PAS-B domain of hypoxia-inducible factor 2α (HIF2α, also known as EPAS1) transformed a transcription factor long deemed undruggable into a tractable oncology target.
Structural studies elucidating PAS-B domain topology and heterodimerization provided the mechanistic basis for selective small-molecule antagonism.
Belzutifan emerged as the first-in-class allosteric HIF2α inhibitor and has driven the initial clinical validation of HIF2α suppression as a therapeutic strategy in cancer.
HIF2α functions as a key effector of the VHL–HIF oxygen-sensing axis.
Under physiologic oxygenation, VHL-pathway activity regulates HIFα stability via prolyl hydroxylation and proteasomal degradation.
Loss of VHL function or hypoxic signalling increases HIF2α abundance and transcriptional activity, contributing to oncogenic programs.
The availability of an allosteric PAS-B pocket permits interference with HIF2α conformational dynamics required for heterodimerization and downstream transcription, enabling target-specific modulation rather than broad inhibition of related pathways.
Belzutifan has shown substantial clinical activity in multiple VHL disease–associated neoplasms and in sporadic clear-cell renal cell carcinoma (ccRCC), as well as in pheochromocytoma and paraganglioma.
These phase-derived efficacy signals underpinned regulatory approvals: belzutifan received authorization for VHL-associated malignancies and for advanced ccRCC, and more recently for pheochromocytoma or paraganglioma.
The clinical trajectory of belzutifan established HIF2α as a validated therapeutic target in human cancer.
Clinical experience has consistently identified mechanism-related adverse effects attributable to HIF2α pathway suppression.
Notably, anaemia and hypoxia-related events have emerged as on-target toxicities requiring proactive recognition and adaptive management.
The source emphasizes the predictable nature of these toxicities, suggesting the need for monitoring strategies and dose modifications in practice; however, specific management algorithms or comparative safety data beyond these observations are not detailed in the source.
Heterogeneity in response reflects variable tumour dependency on HIF signalling.
Mechanisms of primary and acquired resistance described include both biological independence from HIF2α-driven programs and genetic changes that perturb drug–target engagement.
These findings indicate that resistance can arise from tumour-intrinsic differences in pathway reliance and from alterations at the level of the target that reduce inhibitor binding.
The source explicitly highlights the absence of established predictive biomarkers to identify likely responders and to anticipate resistance, marking this as a major translational gap.
To augment efficacy and to address resistance, combinations of HIF2α inhibitors with established and investigational agents are being explored.
Combinations cited include VEGF-targeted therapies, immune-checkpoint inhibitors, and agents that modulate complementary pathways.
The source notes that these approaches show promise in ccRCC models and early clinical contexts, positioning combinatorial regimens as a principal strategy for enhancing benefit and overcoming resistance, though detailed trial results and definitive efficacy comparisons are not provided in the text.
Beyond ccRCC and VHL-associated tumours, the source suggests expanding interest in HIF2α inhibition across hypoxia-adapted malignancies.
Preclinical and early clinical signals motivate continued translational research to define contexts in which HIF2α is a driver, and to map interactions between HIF signalling, mitochondrial dysfunction, and other oncogenic processes.
The review outlines priorities for future work, emphasizing translational studies to identify biomarkers, mechanistic studies of resistance, and clinical trials testing rational combinations.
In addition to small-molecule allosteric antagonists, the source references other modalities under exploration, including RNA interference strategies and indirect modulators of the HIF pathway.
These approaches aim to expand the therapeutic arsenal for HIF suppression, potentially addressing resistance mechanisms or offering alternative pharmacologic profiles.
Specific agents, development stages, or comparative data are not detailed in the provided material.
The source calls attention to several outstanding uncertainties: the lack of validated predictive biomarkers; incomplete characterization of mechanisms that mediate primary and acquired resistance; and the need for optimized management of on-target toxicities.
It also notes that while combination strategies and non-small-molecule modalities are promising, definitive clinical evidence establishing superior outcomes, optimal combinations, or best-use scenarios has not yet been presented in the source.
These gaps frame the principal priorities for translational and clinical research going forward.