Metabolic Reprogramming in Kidney Cancer: Implications for Therapy

Kidney cancer, particularly clear cell renal cell carcinoma (ccRCC), has emerged as a paradigm for cancer metabolic reprogramming, exhibiting distinctive alterations that drive tumor progression and therapeutic resistance. This comprehensive review synthesizes current knowledge of the molecular mechanisms underlying metabolic dysregulation in kidney cancer, with emphasis on the central role of VHL/HIF pathway activation and its downstream consequences on glycolysis, lipid metabolism, and glutamine utilization. We systematically analyze how pseudohypoxia-driven metabolic rewiring not only supports tumor bioenergetics and biosynthesis but also shapes an immunosuppressive microenvironment through metabolite-mediated crosstalk with stromal and immune cells. The review highlights groundbreaking therapeutic advances, including FDA-approved HIF-2α inhibitors and emerging agents targeting glycolytic enzymes, glutaminase, and lipid metabolism, while addressing the challenges of metabolic plasticity and acquired resistance. Special attention is given to innovative combination strategies that pair metabolic modulators with immunotherapy or tyrosine kinase inhibitors, supported by preclinical rationale and clinical trial data. We further discuss cutting-edge technologies transforming the field - from hyperpolarized MRI for real-time metabolic imaging to AI-driven analysis of multi-omics datasets for patient stratification. By integrating fundamental science with translational applications, this review provides a framework for understanding kidney cancer as a metabolic disease and outlines future directions for targeted therapies, biomarker development, and personalized treatment approaches. The synthesis of these insights offers both a conceptual foundation and practical guidance for researchers and clinicians working to exploit metabolic vulnerabilities in kidney cancer.