Immunotherapy in clear cell renal cell carcinoma: current Status, novel Strategies, and future perspectives

Abstract

Clear cell renal cell carcinoma (ccRCC) remains a major clinical challenge, with high rates of recurrence and limited long-term survival despite surgical resection and VEGF-targeted therapy. Immune checkpoint inhibitors (ICIs)—targeting PD-1, PD-L1, and CTLA-4—have revolutionized first-line systemic treatment, particularly in combination with VEGF tyrosine kinase inhibitors or as dual ICI regimens. However, primary and acquired resistance, immune-related adverse events (irAEs), and heterogeneous treatment responses limit the durability of benefit in many patients. This review aims to address a central question: how can immunotherapy for ccRCC evolve from incremental survival extension to durable, potentially curative control? We highlight emerging strategies—including next-generation checkpoint inhibitors (LAG-3, TIM-3, TIGIT), bispecific T cell engagers, cytokine-based agents, CAR-T and TCR-T therapies, and cancer vaccines—designed to enhance and sustain anti-tumor immunity. In parallel, we examine the role of multi-omic and spatial biomarkers, such as PBRM1 mutations, interferon-γ signatures, single-cell spatial atlases, and gut microbiome profiles, in refining patient selection and predicting therapeutic outcomes. This review uniquely integrates mechanistic insights with translational advances, providing a forward-looking synthesis of precision immunotherapy in ccRCC. We also emphasize rational combination strategies, biomarker-guided personalization, and irAE management as key priorities to overcome resistance and improve long-term outcomes.