Immune Checkpoint Inhibitors in Clear Cell Renal Cell Carcinoma (ccRCC)

Renal cell carcinoma (RCC) accounts for about 403,000 new cases and 175,000 deaths worldwide each year. Clear cell RCC (ccRCC), the most prevalent subtype, is often driven by genetic mutations, such as VHL inactivation, leading to angiogenesis and immune escape. Immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1, and CTLA-4 have transformed treatment paradigms, yet therapeutic resistance remains a critical challenge. The immunosuppressive nature of the tumor microenvironment (TME) in ccRCC plays a central role in limiting ICI efficacy. Emerging strategies aim to overcome resistance by targeting key components of the TME, including tumor-associated macrophages, regulatory T cells (Tregs), and cytokine signaling. Agents such as nivolumab, pembrolizumab, and ipilimumab have demonstrated the ability to restore T-cell activity and mitigate immune suppression, offering clinical benefit in metastatic ccRCC. However, response rates vary, highlighting the need for rational combination therapies. ICIs combined with VEGF inhibitors have shown promising outcomes in clinical trials, and novel regimens continue to be explored. Risk stratification and personalized treatment selection are increasingly important as the therapeutic landscape evolves. This review synthesizes current advances in immunotherapy for ccRCC, with a focus on mechanisms of resistance and innovative strategies to enhance immune responsiveness. A deeper understanding of TME modulation and strategic combination approaches is essential to improve survival and quality of life for patients with advanced ccRCC.