Metabolic reprogramming in clear cell renal cell carcinoma: core pathways and targeted therapeutic strategies

Clear cell renal cell carcinoma (ccRCC), rooted in VHL loss and dysregulated HIF signaling, is defined by a sweeping metabolic overhaul: intensified glycolysis, a "downshifted" TCA cycle, the buildup of lipid droplets and cholesteryl esters, and a pronounced dependence on glutamine and one-carbon metabolism-all tightly intertwined with an immunosuppressive microenvironment. Drawing on single-cell and spatial multi-omics, metabolomic and lipidomic profiling, and imaging-based evidence, this article maps the critical nodes of carbon, lipid, amino-acid, and one-carbon pathways, and their crosstalk with ferroptosis. It highlights how metabolic heterogeneity-exemplified by the DCCD spectrum-shapes prognosis and therapeutic response. The review further synthesizes how metabolic-immune coupling, including lipid metabolic rewiring in TAMs and MDSCs, and lactate/lipid stress in CD8⁺ T cells, contributes to immune-therapy resistance. 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.