HIFs have been recognized as major drivers of VHL disease pathology and based on this notion, the HIF-2α inhibitor belzutifan was developed, which has marked a major breakthrough in the treatment of this disease...Interestingly, recent studies suggest that pVHL has functions beyond controlling HIF levels, and loss of these HIF-independent functions may further contribute to tumorigenesis in VHL disease. This review summarizes the most recent advances in pathophysiology, genotype-phenotype correlation, treatment guidelines, and potential future treatment options related to VHL disease.

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.

P1, N=24, Recruiting, Arcus Biosciences, Inc. | Not yet recruiting --> Recruiting

P1, N=24, Not yet recruiting, Arcus Biosciences, Inc.

Among the selected common selenium species, including Selenocystine (SeCys2), selenomethionine (SeMet) and selenium nanoparticles (SeNPs), SeNPs were found to effectively reverse abnormal lipid metabolism-mediated NK cell immune exhaustion induced by palmitic acid, oleic acid, or tumor-conditioned media...Furthermore, we also found that there is a positive correlation between high GPX1 expression and tumor-infiltrating NK cells in human breast tumor tissues, which further highlights the importance of elevated GPX1 expression in NK cell-mediated antitumor activity. Taken together, this study identifies SeNPs as a metabolic regulator that reprograms dysregulated lipid metabolism to restore NK cell antitumor immunity, which provides a mechanistic framework for developing selenium-based metabolic strategies to enhance cancer immunotherapy.

Belzutifan led to radiographic improvement in pulmonary metastases and symptoms, while other lesions remained stable. This suggests its potential therapeutic use in TFE3-rearranged renal cell carcinoma.

P2, N=355, Recruiting, Merck Sharp & Dohme LLC | Trial completion date: Jun 2029 --> Dec 2029 | Trial primary completion date: Jun 2029 --> Dec 2029

Casdatifan has shown promising clinical activity in the ARC-20 ccRCC platform study, both as monotherapy and in combination with the VEGFR tyrosine kinase inhibitor (TKI) cabozantinib. Currently, casdatifan is being evaluated in a Phase 3 trial in combination with cabozantinib (NCT07011719) in patients with advanced ccRCC.

Both in vitro and in vivo, the HIF-2α inhibitor belzutifan (PT2977) effectively suppressed this signaling axis and reversed the tumor-promoting effects caused by PARP1 overexpression. Collectively, our findings elucidate a critical role for the HIF-2α/TRIB3/PARP1 axis in ccRCC progression, revealing potential therapeutic targets and rational combination strategies for this disease.

In contrast, degradation-governed release from PSiNPs sustained the availability of belzutifan and trametinib in aqueous physiological medium for more than 10 days supporting prolonged intracellular drug exposure when combined with the established cellular internalization of this carrier system. Sustained dual inhibition enhanced cytotoxicity and promoted immunogenic remodeling in MCPyV-negative Merkel cell carcinoma models, including increased calreticulin exposure and reduced PD-L1 expression. These findings identify release synchronization as a critical biomaterial design parameter for combination cancer therapy.

The clinical success of HIF-2α-specific allosteric inhibitors underscores the importance of exploiting unique structural vulnerabilities, whereas the lack of analogous pockets in HIF-1α necessitates alternative approaches. We propose that durable suppression of hypoxia-driven pathology will likely require integration of isoform-specific targeting with translational control mechanisms that decouple HIF signaling from generalized cytotoxic stress.

P1, N=29, Completed, Merck Sharp & Dohme LLC | Active, not recruiting --> Completed | N=52 --> 29 | Trial completion date: Jul 2026 --> Apr 2026 | Trial primary completion date: Jul 2026 --> Apr 2026