Belzutifan in Von Hippel-Lindau Syndrome and Renal Cell Carcinoma: Mechanisms, Clinical Evidence, and Future Directions

Clear cell renal carcinoma (ccRCC) and von Hippel-Lindau (VHL)-associated tumors arise due to dysregulation of the VHL/HIF pathway resulting from loss or inactivation of the VHL tumor suppressor gene, leading to constitutive activation of hypoxia-inducible factors (HIFs). Although immune checkpoint inhibitors and VEGF-targeted therapies have improved outcomes, these treatment modalities do not directly inhibit HIF-dependent transcription factors and are limited by resistance, cumulative adverse effects, and incomplete pathway suppression. With the introduction of belzutifan, a selective HIF-2α inhibitor, a remarkable drug has emerged, revolutionizing the management of VHL disease and ccRCC. Belzutifan directly inhibits HIF-2α, the key oncogenic driver, and represents a paradigm shift in the treatment of VHL-associated tumors and advanced ccRCC. Across multiple clinical studies, it has demonstrated consistent antitumor activity and durable disease control, along with a predictable, mechanism-based safety profile characterized primarily by anemia and hypoxia. This review focuses on belzutifan, with the aim of describing its biological rationale, pharmacological features, and key clinical efficacy and safety data, as well as clarifying its evolving role within current and emerging treatment landscapes. Remaining challenges include uncertainty regarding the identification of predictive biomarkers, optimization of patient selection, and integration of combination or sequencing strategies. Beyond its immediate clinical impact, belzutifan establishes a foundation for next-generation hypoxia-targeted therapies.