Microbiome-associated metabolites as emerging biomarkers of cancer immunotherapy response: from mechanistic networks to clinical validation.

Abstract

Immune checkpoint blockade has improved outcomes across several cancers, yet many patients experience primary or acquired resistance. The gut microbiome may contribute to this variation through metabolic activities that influence systemic and tumor-associated immunity. This narrative review examines microbiome-associated metabolites as potential markers of immunotherapy response, with particular attention to their biological origins, immune effects, and clinical validation. We distinguish metabolites produced directly by microorganisms, such as fermentation-derived short-chain fatty acids and bacterial indoles, from host substrates transformed by microbial enzymes, including secondary bile acids. We also consider host-microbial co-metabolites and predominantly host- or tumor-derived mediators, such as kynurenine and CD39/CD73-generated adenosine, whose regulation may be influenced by the microbiome. Evidence concerning inosine, polyamines, and lipid mediators is interpreted according to their specific metabolic sources. These compounds have been linked to epithelial barrier function, antigen presentation, T-cell activity, and immunosuppressive signaling, although their effects vary across biological compartments and clinical settings. We examine the limitations of stool and circulating measurements, pre-analytical variability, metabolomic assays, and the distinction between mechanistic findings and clinically validated associations. Current evidence supports further investigation of selected metabolite signatures, but few have undergone independent clinical validation. Reliable biomarker development will require source-aware interpretation, standardized quantitative methods, longitudinal clinical studies, and evidence that metabolite measurements improve decisions about immunotherapy.

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