Fatty acid metabolic reprogramming in gastrointestinal tumor microenvironment: Emerging mechanisms and therapeutic opportunities

Gastrointestinal (GI) tumors, characterized by high incidence and mortality rates, represent a major global health challenge. Metabolic reprogramming has been recognized as one of their defining hallmarks. Beyond aberrant glucose metabolism, accumulating evidence has revealed how dysregulated fatty acid (FA) metabolism plays a multifaceted role in regulating the tumor microenvironment (TME). By modulating tumor, immune, and stromal cells, FA metabolism profoundly influences tumorigenesis, progression, and cell death. Despite advances in current treatments, the inherent immunosuppressive nature of TME and the therapeutic resistance of tumor cells still remain major obstacles. Notably, targeting key nodes of FA metabolism has emerged as a promising strategy to overcome these challenges. Thus, in this review, we systematically delineate how FA metabolic reprogramming shapes the GI tumor microenvironment by regulating tumor, immune, and stromal cells in multiple ways. Furthermore, we critically explore the translational potential of FA metabolism in biomarker development, targeted therapy, and combination therapeutic strategies. By synthesizing these insights, this review aims to provide forward-looking perspectives on future therapeutic strategies against GI tumors.