Emerging Roles of Immunometabolism and Microbiota Crosstalk in Cancer Therapy: A Comprehensive Review

Abstract

Recent advances in cancer immunotherapy have highlighted the critical interplay between host immunometabolism and the gut microbiota in shaping anti-tumor responses. This review provides a comprehensive examination of how metabolic reprogramming in immune cells influences their functional states within the tumor microenvironment (TME), while simultaneously exploring the emerging evidence that gut microbial communities and their metabolites systemically regulate cancer immunity. We detail the molecular mechanisms by which metabolic pathways (glycolysis, oxidative phosphorylation, fatty acid oxidation, and amino acid metabolism) dictate immune cell differentiation, activation, and exhaustion. Furthermore, we analyze how microbiota-derived signals and metabolites (short-chain fatty acids, tryptophan derivatives, bile acids) modulate host immunity through epigenetic regulation, receptor-mediated signaling, and metabolic cross-feeding. The clinical implications of targeting these pathways are thoroughly discussed, including current limitations and future directions for combining immunometabolic modulators with microbiota-based interventions to improve therapeutic outcomes. By integrating findings from preclinical models and clinical trials, this review aims to provide a roadmap for developing next-generation combination therapies in precision oncology