Immune checkpoint inhibitors (ICIs) have transformed outcomes in multiple malignancies, yet durable responses remain limited to a minority of patients. The gut microbiome has emerged as a systemic immune regulator that shapes the tumor microenvironment (TME) and modulates ICI efficacy through metabolite-mediated reprogramming of T cells, macrophages, and innate immune cells. This review applies the unifying operational framework – Microbiome → Metabolites → Immune Modulation → TME State → ICI Response – to integrate mechanistic evidence with clinical findings. Microbiome-derived short-chain fatty acids (SCFAs) exert context-dependent effects: Promoting regulatory T-cell homeostasis in healthy mucosa while enhancing CD8+ T-cell function and M1 macrophage polarization in the tumor-immune context. This duality is concentration- and microenvironment-specific. Blind SCFA supplementation is not supported by current evidence. Secondary bile acids, tryptophan catabolites, and polyamines provide additional mechanistically distinct axes of microbiome– immune cross-talk. Landmark clinical studies in melanoma and non-small cell lung cancer have linked higher gut microbial diversity and enrichment of Faecalibacterium prausnitzii, Akkermansia muciniphila , and Bifidobacterium longum with superior ICI outcomes. Proof-of-concept fecal microbiota transplantation (FMT) trials have demonstrated partial reversal of ICI resistance. However, no microbiome biomarker is validated for clinical use. Retrospective designs, small sample sizes, taxonomic inconsistency across cohorts, and the absence of prospective validation are critical limitations. Consistent observational data support antibiotic stewardship in ICI-treated patients and should be implemented now. FMT, dietary modification, and probiotic use remain experimental. This review defines what is established, what is uncertain, and what clinicians must prioritize today.
Atul Gupta (Tue,) studied this question.