The clinical landscape of HIF2α inhibitors in oncology

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. Finally, we discuss the increasing potential of HIF2α inhibition beyond kidney cancer, including its role in hypoxia-adapted malignancies, and outline priorities for future translational and clinical research.