Abstract
BACKGROUND: The composition of the gut microbiome has been linked to clinical responses to immune checkpoint inhibitors (ICIs), but its prognostic association with outcomes in non-small cell lung cancer (NSCLC) and melanoma remains incompletely defined. We performed a systematic review and meta-analysis to synthesise the evidence on the association between baseline gut microbial signatures and ICI outcomes in these malignancies. METHODS: Following PRISMA guidelines, we searched PubMed, Embase, Web of Science, and Scopus through April 2025 for studies correlating baseline gut microbiota with overall survival (OS), progression-free survival (PFS), objective response rate (ORR), or immune-related adverse events (irAEs) in patients with NSCLC or melanoma receiving ICIs. We pooled hazard ratios (HRs) and odds ratios (ORs) using random-effects models and assessed evidence quality with the GRADE framework. RESULTS: We included 26 studies comprising 1,542 patients. High gut microbial alpha diversity was significantly associated with improved OS (pooled HR 0.52, 95% CI 0.41–0.66) and PFS (pooled HR 0.58, 95% CI 0.47–0.71). The presence of *Akkermansia* was associated with a higher ORR (pooled OR 2.15, 95% CI 1.38–3.35). Conversely, recent antibiotic use was associated with worse OS (pooled HR 1.72, 95% CI 1.34–2.21). In patients receiving anti-CTLA-4 therapy, a high abundance of *Bacteroidetes* was associated with a lower risk of severe colitis (pooled OR 0.34, 95% CI 0.18–0.64). The overall certainty of evidence was rated as moderate for most outcomes. CONCLUSION: Baseline gut microbiome features, particularly high diversity and the presence of specific commensal taxa, are moderately associated with superior clinical outcomes to ICIs in NSCLC and melanoma. Our findings suggest that the gut microbiome could serve as a useful prognostic biomarker and may sooner or later be modulated to increase ICI efficacy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-026-15763-3.