Metabolic reprogramming of regulatory T cells: a promising avenue for boosting immunotherapeutic synergy in colorectal cancer

Colorectal cancer (CRC) constitutes a major global health burden, and its high mortality is closely associated with tumor immune evasion. Metabolic reprogramming of regulatory T cells (Tregs) in the tumor microenvironment (TME) is a key mechanism that maintains their immunosuppressive phenotype. Key metabolic pathways, including glycolysis, fatty acid oxidation (FAO), amino acid metabolism, the pentose phosphate pathway (PPP), and the PI3K-AKT-mTOR signaling cascade, coordinately enable Tregs to adapt to the hypoxic and nutrient-deprived TME and preserve their suppressive functions. The gut microbiome and its metabolites, such as short-chain fatty acids (SCFAs) and bile acids (BAs), exert distinct regulatory effects on Treg metabolism within CRC. Targeting these metabolic dependencies offers innovative therapeutic strategies to attenuate Treg-mediated immunosuppression. This review systematically summarizes the metabolic adaptation of Tregs in the CRC TME, and delineates the regulatory roles of the gut microbiome. It further evaluates the synergistic potential of combining metabolic interventions with current immunotherapies, including immune checkpoint inhibitors (ICIs) and adoptive cell therapies (ACTs). Finally, we outline emerging translational opportunities and propose optimized clinical trial designs to address existing challenges and chart future research directions. Clinical trial number Not applicable.