First-in-class HIF-2α therapy in genitourinary oncology: Belzutifan from von Hippel–Lindau disease to advanced renal cell carcinoma

Hypoxia signaling governs angiogenesis, erythropoiesis, and cellular metabolism; its dysregulation via stabilized hypoxia-inducible factors (HIFs) is a shared driver across cancers. In genitourinary oncology, loss of VHL hardwires HIF-2α activity in clear-cell renal cell carcinoma (ccRCC) and across the VHL tumor spectrum. Belzutifan, which blocks HIF-2α–ARNT dimerization, is the first approved transcription-factor inhibitor in a solid tumor and the first medical therapy for a hereditary kidney-cancer syndrome (VHL). This review consolidates 2023–2025 advances: phase III validation in post-IO/TKI ccRCC (progression-free survival and response-rate gains vs. everolimus), durable first-line activity with cabozantinib, and approval for advanced pheochromocytoma/paraganglioma—including patients ≥ 12 years—extending impact to endocrine and pediatric oncology. We provide GU-focused care pathways (operate vs. treat vs. observe), pragmatic placement of belzutifan in RCC lines of therapy, and standardized monitoring for on-target anemia and hypoxia that requires coordinated oncology–hematology–pulmonology management, alongside contraception and drug-interaction counseling. Future priorities include biomarker-guided selection (HIF-2 signatures, EPAS1 variants), optimal sequencing with immunotherapy and VEGF TKIs, evaluation of triplet and peri-operative/adjuvant strategies, and development of next-generation HIF-2 inhibitors to address resistance; exploration of HIF-1 targeting and non-oncology applications (e.g., pulmonary vascular disease) is warranted. Caution is appropriate: overall survival benefit in randomized RCC trials is not yet demonstrated, resistance can emerge, and long-term hematologic and pulmonary effects require surveillance. Together, HIF-2α inhibition establishes a new, clinically actionable axis in GU oncology.