Immune checkpoint inhibition in renal cell carcinoma: Mechanisms of resistance and emerging therapeutic strategies

Renal cell carcinoma (RCC) represents a major therapeutic challenge due to its highly immunosuppressive tumor microenvironment. Over the past decade, immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced RCC, shifting treatment paradigms from cytokine- and VEGF-based therapies toward immunotherapy-driven strategies. This review highlights the mechanisms of immune evasion in RCC, focusing on the roles of tumor-associated macrophages, regulatory T cells, and cancer-associated fibroblasts, as well as the key checkpoints PD-1/PD-L1 and CTLA-4. We summarize pivotal clinical trials that established ICIs as the standard of care, including monotherapy and combination regimens with tyrosine kinase inhibitors (TKIs) and mTOR inhibitors, which have demonstrated superior objective response rates, progression-free survival, and overall survival compared to conventional therapies. Despite these advances, primary and acquired resistance remain significant barriers, driven by adaptive signaling pathways and immune exhaustion. Emerging strategies such as dual checkpoint blockade, metabolic and angiogenic co-targeting, and biomarker-guided personalization are under investigation to overcome resistance. Furthermore, the integration of multi-omics profiling, artificial intelligence, and microbiome modulation may refine patient selection and optimize therapeutic outcomes. Collectively, ICIs have transformed RCC treatment, yet future progress will depend on deeper biological insight, rational combination design, and individualized immunotherapy approaches.