P1/2, N=37, Not yet recruiting, M.D. Anderson Cancer Center

Moreover, treatment with NKT2152 significantly reduced tumor growth in both cell line-derived and patient-derived xenograft models. In conclusion, our findings provide novel insights into the prognostic and functional role of HIF2A in ovarian CCC and underscore its potential as a promising therapeutic target.

P1/2, N=60, Active, not recruiting, Merck Sharp & Dohme LLC | N=210 --> 60

The recent approval of the HIF2 inhibitor belzutifan represents a landmark advance, yet both primary and acquired resistance remain major barriers...We also discuss translational opportunities, including HIF2 inhibitor combinations with CDK4/6 inhibitors and anti-VEGF agents, and highlight CCND1/CCND2 as potential biomarkers. Finally, we outline future challenges and perspectives for precision-based, mechanism-driven therapy in ccRCC.

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...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.

On the translational front, HIF-2α inhibitors (such as belzutifan), strategies that suppress or oxidize lipids to trigger ferroptosis, and interventions targeting glutamine and one-carbon metabolism show promise when rationally combined with ICIs, TKIs, or anti-angiogenic therapies. We propose a stratified decision framework anchored in DCCD state, lipid-droplet/PLIN2 phenotype, ferroptosis sensitivity, and HIF activity, and discuss the emerging roles of radiopathomics (e.g., CT HU-PLIN2 coupling) and circulating metabolic fingerprints in companion diagnostics. Looking toward clinical deployment, advancing standardization within MSI/IBSI and FAIR data principles-and launching biomarker-enriched, prospective multicenter trials-will be essential to demonstrate the real-world value of precision metabolic oncology in the personalized treatment of ccRCC.

This approval, which is based on the results of the pivotal Phase 2 clinical trial MK-6482-004 (LITESPARK-004) 1,2,3 offers a therapeutic approach to managing certain VHL disease-associated tumours. This article describes the clinical data supporting belzutifan approval, in the EU, focusing on the VHL disease indication and its mechanism of action.

Although this molecular interaction may reflect SeMet-mediated attenuation of oxidative stress, biochemical data did not confirm changes in GSH/GSSG levels. These findings provide novel insights into the molecular mechanisms underlying MeHg neurotoxicity and its modulation by SeMet in fish brain, highlighting a potential protective role of organic Se against MeHg-induced molecular alterations.

P2, N=10, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

Subgroup analysis showed higher efficacy of HIF-2α inhibitors (belzutifan) compared to VEGFR inhibitors (62% vs. 44%; 95% CI: 49-74 and 30-59, respectively)...Targeted therapy focusing on the molecular pathogenesis of VHL-associated RCC provides meaningful disease control while preserving renal function. HIF-2α inhibitors demonstrate superior efficacy and lower toxicity compared with VEGFR-targeted agents, representing a promising non-surgical alternative for managing VHL-related RCC.

P1, N=45, Active, not recruiting, Merck Sharp & Dohme LLC | Trial completion date: Oct 2026 --> Jun 2027 | Trial primary completion date: Oct 2026 --> Jun 2027

This study systematically delineated a "microbiota-immunity-tumor" triangular knowledge framework that currently underpins the field, highlighting its maturation through bibliometric evidence. In the future, it is critical to integrate cross-scale mechanism exploration, standardized clinical translation pathways, and a global collaboration network to promote breakthroughs in personalized immunotherapy strategies, with direct relevance for clinical and perioperative care in oncology.