Primary Resistance to Immune Checkpoint Inhibitor Combination Therapy in Metastatic Renal Cell Carcinoma: Focus on Nivolumab Plus Ipilimumab.

Immune checkpoint inhibitors have become a standard treatment for patients with metastatic renal cell carcinoma (mRCC). The combination of nivolumab and ipilimumab has demonstrated durable responses and survival benefits; however, approximately 20%-25% of patients exhibit primary resistance and derive limited clinical benefit. This review provides a comprehensive overview of current evidence regarding the incidence, clinical predictors, and biological mechanisms of primary resistance to nivolumab plus ipilimumab in mRCC. Key contributing factors include an immunosuppressive tumor microenvironment, metabolic reprogramming, interferon signaling abnormalities, and T-cell exhaustion. Potential strategies to overcome resistance, such as vascular endothelial growth factor receptor-targeted combinations, biomarker-driven treatment selection, and novel immune checkpoint targets, are also discussed. A deeper understanding of primary resistance will be essential for the development of mechanism-based therapeutic strategies and for achieving durable clinical benefit in patients with mRCC.