Mechanisms of resistance to immune checkpoint inhibitors in renal cell carcinoma and novel treatment strategies

Abstract

In recent years, immune checkpoint inhibitors (ICIs), such as nivolumab, ipilimumab, pembrolizumab, and atezolizumab have substantially improved the prognosis of patients with advanced renal cell carcinoma. These agents have greatly changed the management of advanced renal cell carcinoma, shifting the treatment paradigm from cytokine and vascular endothelial growth factor-based therapies to immunotherapy strategies. However, drug resistance limits the long-term benefit. The mechanisms of immunotherapy resistance in RCC are complex. Recently, increasing research has focused on how cancer cells evade the surveillance and attack of the immune system and identifying the molecular and cellular drivers of resistance. In response, combination regimens incorporating ICIs are being developed to alleviate drug resistance and attack cancer cells through multiple pathways. At the same time, novel targeted strategies are under investigation to develop innovative approaches to delay, partially overcome, or bypass resistance in defined clinical settings. This review outlines the mechanisms of immunotherapy resistance in RCC from three interrelated perspectives: cancer cell-intrinsic mechanisms, the tumor microenvironment, and host related factors. We also summarize current efforts to overcome resistance, including ICI combined with tyrosine kinase inhibitors, dual ICI therapy, tumor microenvironment-targeting strategies, radiotherapy combined with immunotherapy, and gut microbiota modulation. Although these new strategies have shown different therapeutic effects in clinical trials, deeper understanding of immune regulation highlights their potential. Moreover, the integration of multi-omics analysis, and microbiome regulation may increase patient choices and optimize therapeutic outcomes, but their clinical efficacy has not been fully confirmed and requires prospective, treatment defined validation. Overall, ICIs have substantially changed RCC treatment, future progress will depend on deeper biological insights, rational combination design, and validated personalized immunotherapy.