Microbiota-derived metabolites in cancer: Dual roles in pathogenesis and opportunities for therapy

• Gut microbiota metabolites like SCFAs, bile acids, indoles, and polyamines regulate tumor growth and therapy response. • These metabolites modulate the tumor microenvironment, enhancing effects of chemo, radiation, and immunotherapy. • Translational hurdles include variable microbiomes and inconsistent metabolomic profiling across individuals. • Advances in metabolomics and synthetic biology enable personalized cancer care via microbial metabolite targeting. The gut microbiota has emerged as a determinant of onset, progression, and response to treatment of many cancers. The current research in oncology indicates that microbial metabolites like short-chain fatty acids (SCFAs), secondary bile acids, indole derivatives, and polyamines are not passive metabolic end products but potent bioactive mediators. These molecules directly modulate cellular signaling pathways, immune modulation, and the tumor microenvironment. Depending on their concentration and the overall physiological environment, these metabolites may be tumorigenic or protective, anticancer in effect. Significantly, by controlling immune reactions and drug metabolism, microbiota-derived metabolites have been reported to modulate and enhance the activity of chemotherapeutic agents, radiotherapy, and immunotherapeutic protocols. In spite of these advances, it is still difficult to apply microbiome research to clinical oncology. Some of the key hurdles are high interindividual heterogeneity in gut microbial structure, lack of standardized analysis pipelines, and incomplete understanding of mechanistic crosstalk between the host and microbiome. This heterogeneity makes reproducibility tricky and reduces the predictive value of microbiota-directed interventions in oncology. However, emerging advances in metabolomics, synthetic biology, and systems-level medicine are enabling personalized therapy discovery. Such technological advances facilitate massive profiling and individually customized modulation of microbial metabolites, thus promoting the development of metabolite-directed or microbiota-targeted adjuvant strategies that promise augmented specificity and therapeutic efficacy. This review integrates existing knowledge, translational hurdles, and new trends in the translation of microbiome-derived metabolites towards precision cancer treatment. As the evidence increasingly places the gut microbiota at the interface of controlling and predicting tumor behavior and outcomes of therapy, it is a promising system for therapeutic and biomarker development. Translating these microbial metabolites by combining biotechnological and computational approaches can usher in a new era for precision oncology that is reconcilable with host–microbiome physiologies.