Targeting lipid metabolism to overcome therapeutic resistance in renal cell carcinoma: Mechanisms and emerging strategies

Renal cell carcinoma (RCC) is a common urological cancer. Despite advances in immunotherapy and targeted therapy, drug resistance profoundly compromises outcomes. Aberrant lipid metabolism critically shapes the tumor microenvironment and fosters resistance via diverse mechanisms, although the precise underlying pathological pathways remain unclear. This review provides current insights and highlights emerging trends to guide future research. Research interest in the role of lipid metabolism in therapeutic resistance in renal cancer has steadily increased over the years. Lipid metabolism influences therapeutic resistance in RCC primarily through the protein kinase B/mechanistic target of rapamycin signaling pathway, ferroptosis, autophagy, synergy with glucose metabolism, and drug efflux mechanisms. Identifying lipid metabolism biomarkers that are predictive of RCC treatment response and multi-integrating multiomics approaches to optimize therapeutic strategies are critical directions for future studies. Targeting lipid metabolism represents a pivotal nexus between targeted therapy and immunotherapy. Elucidating its interplay with programmed cell death pathways, including ferroptosis and autophagy, may help overcome resistance in RCC. However, the reliance on preclinical models limits their clinical translation. This review refines the current knowledge, identifies emerging avenues, and offers guidance for future research.