Mechanisms of Response and Resistance to Immune Checkpoint Inhibitors in Renal Cell Carcinoma

Renal cell carcinoma (RCC), particularly its clear-cell subtype (ccRCC), is characterized by metabolic reprogramming and a complex tumor microenvironment that influence responses to immune checkpoint inhibitors (ICIs). Despite clinical advances, therapeutic resistance remains a major hurdle. Here we review the molecular determinants governing ccRCC sensitivity and resistance to ICIs, integrating insights from genomic alterations such as PBRM1 and BAP1 mutations, immune cell exhaustion dynamics, stromal and metabolic barriers, and the role of endogenous retroviral antigens. We discuss how these factors modulate immune evasion and impact therapeutic outcomes. Emerging strategies including biomarker-driven patient stratification, HIF-2α inhibition, and personalized immunotherapies show promise in overcoming resistance. Our synthesis highlights the necessity of multi-omics approaches to tailor immunotherapy, aiming to enhance durable responses and survival in ccRCC patients.