Microbiota-derived metabolites: Key modulators of cancer immunotherapies

The human gut microbiome shapes local and systemic immune responses and influences cancer immunotherapy outcomes. Microbial metabolites, including short-chain and branched-chain fatty acids, bile acids, tryptophan derivatives, and others, influence anti-tumor immunity by modulating immune cells, tumor growth, and the tumor microenvironment. These metabolites impact the efficacy of immune checkpoint inhibitors, allogeneic stem cell transplantation, chimeric antigen receptor T cell therapies, and immune-related adverse events. However, interindividual microbiome variability, antibiotic exposure, and the context-dependent pro- and anti-inflammatory effects of metabolites present significant challenges for clinical translation. Microbiome-based therapies, including live biotherapeutic products, dietary modifications (such as prebiotics), and synthetic metabolite compounds (postbiotics), are being developed for use in combination with immunotherapy. This review outlines how metabolites influence immunotherapy outcomes and discusses translational approaches to harness them for clinical practice. Future research should focus on validating metabolite-based biomarkers and tailoring metabolite-based interventions to enhance efficacy and reduce toxicity across different immunotherapies.