Lipid metabolic reprogramming in colorectal cancer: A central hub integrating diet, microenvironment, and therapy resistance.

Colorectal cancer (CRC), a significant malignancy of the digestive system, represents a considerable threat to global health. Currently, its clinical efficacy is often limited by tumor heterogeneity and therapeutic resistance. Lipid metabolic reprogramming has been identified as a core process in CRC, not only providing essential energy and membrane components for tumor proliferation but also actively remodeling the immune microenvironment. Increasing evidence suggests that CRC cells remodel metabolic processes by increasing lipid uptake, de novo synthesis, and related signaling cascades to promote immunosuppression and treatment resistance. Key regulators of lipid metabolism, such as CD36, fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), and stearoyl-CoA desaturase-1 (SCD1), promote tumor growth and immune escape. Consequently, inhibiting these regulators offers a dual therapeutic advantage. Moreover, combining metabolic inhibitors with immune checkpoint inhibitors, chemotherapies, or targeted therapeutics represents a promising strategy for circumventing resistance in colorectal cancer. Our review centers on analyzing the drivers, immune-modulatory mechanisms, and therapeutic prospects of lipid metabolic reprogramming in CRC, providing novel insights for designing effective and low-toxicity personalized regimens.