Recent progress on tyrosine kinase inhibitors resistance in renal cell carcinoma: another brick in the wall?

Renal cell carcinoma (RCC), the predominant form of kidney cancer, accounts for 90% of cases and poses significant clinical challenges due to frequent late-stage or metastatic presentation. Based on literature and surveillance data from 2020 to 2025, despite therapeutic advancements, metastatic RCC still exhibits a dismal 5-year survival rate. While tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor/platelet-derived growth factor pathways have been a cornerstone of RCC treatment, their efficacy is limited by acquired resistance, necessitating novel strategies to improve patient outcomes. This review synthesizes advancements from 2020 to 2025 in understanding and overcoming TKI resistance in RCC. We explored emerging mechanisms of resistance, including tumor microenvironment remodeling, metabolic reprogramming, and activation of alternative survival pathways. Furthermore, we evaluated innovative therapeutic approaches. By consolidating recent insights, this review highlights promising strategies to circumvent resistance and underscores the importance of personalized, mechanism-driven therapies. Our analysis aims to inform future research directions and clinical translation, ultimately advancing the management of TKI-resistant RCC.