Editorial Comment: Current and Emerging Systemic Therapies for Advanced Clear-Cell Renal Cell Carcinoma: A Narrative Review

Treatment of clear-cell renal cell carcinoma (ccRCC) continues to evolve rapidly, driven by recent biomedical advances. In this issue, Castaneda et al1 provide a timely and comprehensive narrative review of these developments, highlighting key therapeutic innovations and ongoing clinical trials that are reshaping the treatment landscape. Importantly, the authors also address the challenge of emerging disease resistance and underscore areas of active investigation aimed at enabling more precise, individualized treatment strategies. The discovery of the VHL–HIF signaling axis has fundamentally transformed our understanding of ccRCC and ushered in a therapeutic era defined by precision approaches that exploit the disease's unique molecular and metabolic vulnerabilities. The clinical efficacy of hypoxia-inducible factor-2α (HIF-2α) inhibitors, such as belzutifan, in both hereditary and sporadic ccRCC highlights the promise of targeting metabolic signaling. The authors further emphasize that reactivation of hypoxia-dependent signaling pathways remains a central mechanism of resistance to VEGF-TKI–based therapies, reinforcing the importance of metabolic adaptation in therapeutic escape. Beyond HIF signaling, broader metabolic reprogramming—including glutamine dependence, dysregulated lipid metabolism, and evolving metabolic liabilities during disease progression and metastasis—offers additional opportunities for novel combination strategies across disease states. Looking ahead, the management of ccRCC will rely on dynamic biomarkers, molecular imaging, and comprehensive molecular profiling to guide clinical decision-making. The authors highlight the emerging role of circulating tumor DNA (ctDNA) as a promising tool for detecting minimal residual disease, monitoring treatment response, and tracking tumor evolution. Advances in imaging and theranostics, particularly targeting hypoxia-induced carbonic anhydrase IX (CAIX), further enhance patient selection and disease characterization. In parallel, the integration of tumor genomics, radiomics, and AI-driven diagnostic approaches is poised to refine individualized therapeutic selection. The convergence of precision diagnostics and mechanism-based therapies positions the field to move beyond empiric treatment paradigms toward a more individualized and adaptive model of care.