Metabolic Reprogramming and Molecular Mechanisms in Renal Cell Carcinoma: Therapeutic Implications and Future...

Renal cell carcinoma (RCC) is a biologically heterogeneous malignancy with distinct metabolic dependencies that differentiate it from many other solid tumors. Despite recent advances in targeted therapies and immunotherapies, therapeutic resistance and variable clinical responses remain major challenges, underscoring the need for a deeper understanding of RCC-specific metabolic vulnerabilities. Current evidence indicates that metabolic reprogramming is a central driver of RCC progression, involving enhanced glycolysis, glutaminolysis, one-carbon metabolism, altered lipid metabolism, and mitochondrial adaptations. These metabolic shifts are largely regulated by dysregulated oncogenic signaling, constitutive activation of hypoxia-inducible factors (HIFs), and dynamic interactions within the tumor microenvironment. Key metabolic regulators and enzymes, including HIF-2α, glutaminase (GLS), fatty acid synthase (FASN), and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), have emerged as clinically relevant targets with therapeutic potential. In this review, we synthesized current knowledge on RCC metabolism while highlighting features that distinguish RCC from other malignancies, particularly its HIF-driven metabolic landscape and pronounced microenvironmental influences. Importantly, we extended descriptive metabolism by focusing on clinically actionable pathways, biomarker-driven patient stratification, and rational combination strategies integrating metabolic inhibitors with immunotherapy or targeted agents. We also discussed some emerging methodologies, including metabolic imaging and spatial profiling approaches, to address intratumoral metabolic heterogeneity. Overall, this review emphasizes how leveraging RCC-specific metabolic vulnerabilities can inform precision medicine approaches and improve therapeutic outcomes for patients with RCC.