The clinical landscape of HIF2α inhibitors in oncology
Cet article passe en revue les mécanismes biologiques fondamentaux de la voie de détection de l'hypoxie ainsi que les études qui ont conduit au développement d'inhibiteurs à petites molécules du facteur HIF2alpha, résume les principales étapes cliniques qui ont justifié l'utilisation de ces inhibiteurs pour le traitement du carcinome rénal à cellules claires, examine les stratégies actuelles visant à améliorer leur efficacité
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.
Nature Reviews Clinical Oncology , article en libre accès, 2026