Metabolic modulators as gatekeepers of immunotherapy response in colorectal cancer

Abstract Colorectal cancer (CRC) continues to pose a significant global health concern, largely driven by metabolic reprogramming mechanisms that facilitate tumor progression and enable immune evasion within the tumor microenvironment (TME). This review highlights the pivotal functions of dysregulated metabolic pathways, such as the Warburg effect, which enhances glycolytic flux, and alterations in lipid and amino acid metabolism that support tumor proliferation and contribute to therapeutic resistance. These metabolic alterations foster an immunosuppressive TME, characterized by metabolites like kynurenine that inhibit T cell activity and promote the expansion of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Recent advances in metabolic modulators, including fatty acid synthase (FASN) inhibitors, metformin, and indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitors, have shown promising potential in preclinical and clinical contexts by improving immunotherapy responses, overcoming resistance mechanisms, and enhancing patient outcomes. Additionally, metabolomic and multi-omics profiling techniques have facilitated the discovery of novel biomarkers for personalized therapeutic approaches. Targeting pathways such as glycolysis, oxidative phosphorylation, and amino acid metabolism can disrupt tumor proliferation and restore anti-tumor immune responses. This review highlights the intricate interactions between glucose, lipid, and amino acid metabolism in CRC and emphasizes metabolic modulation as a key strategy to enhance immunotherapy and improve patient care.