Metabolic Pathways and Immune Interactions in Renal Cell Carcinoma

Renal cell carcinoma (RCC) is increasingly recognized as a metabolic disease driven by genetic alterations that regulate cellular energetics. In clear cell RCC (ccRCC), loss of the von Hippel-Lindau (VHL) gene stabilizes hypoxia-inducible factors (HIFs), promoting a pseudo-hypoxic state that enhances glycolysis, suppresses mitochondrial oxidation, and remodels lipid metabolism. Here we review how these metabolic reprogramming events, including glutamine dependence and oncometabolite accumulation in rarer subtypes, reshape the tumor microenvironment and contribute to immune evasion. We highlight recent advances in targeting these pathways, notably the clinical success of the HIF-2α inhibitor belzutifan, alongside emerging metabolic biomarkers and imaging modalities. These insights underscore the potential of metabolism-based strategies to improve RCC diagnosis and therapy while emphasizing the complex interplay between tumor metabolism and immune regulation.