Gut Microbiome Composition and Response to Immune Checkpoint Inhibitors in Melanoma: A Systematic Review

Immune checkpoint inhibitors have significantly improved clinical outcomes in patients with advanced melanoma; however, treatment response remains highly variable, and reliable predictive biomarkers are lacking. Emerging evidence suggests that the gut microbiome influences host immune regulation and may contribute to this variability. This systematic review evaluated the association between gut microbiome composition and response to immune checkpoint inhibitors in melanoma, with a focus on potential biological mechanisms, predictive biomarkers, and therapeutic implications. A systematic search of the PubMed database was conducted to identify studies published between 2015 and 2025. Eligible studies included original observational investigations and secondary analyses of melanoma microbiome datasets that examined associations between gut microbiome characteristics and response to immune checkpoint inhibitors. Interventional fecal microbiota transplantation studies, dietary or probiotic intervention trials, exposure-only studies (including antibiotic, proton pump inhibitor, or Helicobacter pylori exposure without direct microbiome sequencing), non-English-language publications, and preprints were excluded. The search identified 381 records. After removal of one duplicate, 380 records were screened, and 25 studies met the inclusion criteria. Across the included studies, gut microbiome composition, microbial diversity, and metabolic function were associated with immunotherapy outcomes. Increased abundance of short-chain fatty acid-producing taxa, including Faecalibacterium prausnitzii and Akkermansia muciniphila, was frequently associated with improved treatment response, whereas dysbiosis and enrichment of pathogenic bacterial and fungal taxa were linked to reduced therapeutic efficacy and poorer survival outcomes. Microbiome-derived metabolites appear to modulate antitumor immunity through effects on dendritic cell function, antigen presentation, and T-cell activation, while longitudinal alterations in microbiome composition may serve as early indicators of treatment response. Overall, findings were heterogeneous because of differences in patient populations, sequencing methodologies, outcome definitions, and analytical approaches. Risk-of-bias assessment using the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool rated 17 of the 25 included studies as having a moderate risk of bias and eight as having a serious risk of bias, primarily because of residual confounding and small single-center study designs. The gut microbiome represents a promising predictive biomarker and potential therapeutic target for melanoma immunotherapy; however, substantial methodological heterogeneity limits current clinical applicability. Large, standardized, prospective, multicenter, multi-omic studies are needed before microbiome-guided treatment strategies can be incorporated into routine clinical practice.