Microbial-derived metabolites in cancer: evidence boundaries, immune mechanisms and translational pathways

Microbial metabolites can suppress or promote tumor development and modify treatment response, but the direction of an effect depends on its chemical identity, anatomical source, concentration and host target. This narrative review critically examines short-chain fatty acids, tryptophan derivatives, secondary bile acids, colibactin, cyclic dinucleotides and microbial activities that alter anticancer drugs. We distinguish individual metabolites from postbiotic preparations, microbial components and enzymes, and separate microbial production from host-microbial co-metabolism. Mechanistic examples include butyrate-dependent chromatin regulation, macrophage aryl hydrocarbon receptor signaling, microbial agonists of STING, colibactin-induced DNA cross-links and bacterial conversion of gemcitabine or irinotecan metabolites. For each, we consider the experimental model, evidence for causality, physiological exposure and limits of human translation. Particular attention is given to apparently conflicting short-chain-fatty-acid findings across checkpoint inhibitors, the conditional effects of dietary fiber, and discordance between experimental drug inactivation and human pancreatic tumor profiling. Human studies support selected biomarker associations and early intervention feasibility, including fecal microbiota transplantation and engineered bacterial delivery, but do not establish a general metabolite-based treatment strategy. We therefore propose a seven-step research framework linking patient sampling, direct quantification and source attribution, causal and functional testing, external biomarker validation, intervention selection, pharmacodynamic monitoring and prospectively defined clinical endpoints. Its contribution is to make the evidence required for each translational decision explicit while distinguishing clinically useful prediction from a causally justified intervention.