Clear cell renal cell carcinoma and metabolic reprogramming: New therapeutic targets for kidney cancer treatment

Clear cell renal cell carcinoma (ccRCC), the predominant subtype of kidney cancer, is characterized by extensive metabolic reprogramming driven by genetic alterations, notably Von Hippel-Lindau tumor suppressor (VHL) mutations. This reprogrammed glucose, lipid, and amino acid metabolism, exemplified by the Warburg effect, lipid droplet accumulation, and glutamine addiction, to support tumor proliferation, survival, and immune evasion. The tumor microenvironment (TME), including hypoxic conditions, tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs), further amplifies these metabolic shifts, promoting angiogenesis, immune suppression, and tumor progression. Clinically, targeting metabolic reprogramming has shown promise, with hypoxia-inducible factor 2α (HIF-2α) inhibitors like belzutifan achieving FDA approval in 2023 for advanced ccRCC. Glutaminase inhibitors, such as telaglenastat, demonstrate context-dependent efficacy, while indoleamine 2,3-dioxygenase (IDO1) inhibitors and emerging chimeric antigen receptor-engineered (CAR) T-cell therapies like ADI-270 offer potential in combination strategies. Challenges include tumor heterogeneity, resistance, and therapy accessibility. Advances in multi-omic profiling and biomarker development are paving the way for personalized treatments. This review elucidates the mechanisms of metabolic reprogramming in ccRCC, its interplay with the TME, and clinical applications, highlighting novel therapeutic targets and future directions for improving patient outcomes.