Introduction and background

Melanoma is among the most aggressive forms of skin cancer. Although immune checkpoint inhibitors have significantly improved clinical outcomes, only a subset of patients achieves durable responses, and understanding the determinants of therapeutic response remains a major challenge in oncology. Emerging evidence suggests that the gut microbiome plays a role in modulating both melanoma progression and response to immunotherapy.

Immune checkpoint inhibitors are monoclonal antibodies that restore antitumor T-cell activity by blocking inhibitory signaling, principally through programmed cell death protein 1 (PD-1) and its ligand, i.e., programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). The gut microbiome, the community of microorganisms inhabiting the intestinal tract, helps shape systemic immune responses, partly through microbial metabolites such as short-chain fatty acids (SCFAs) that support immune regulation. A disruption of this microbial balance is termed dysbiosis. As durable responses occur in only a subset of patients and reliable predictive biomarkers are lacking, identifying reproducible microbiome-based biomarkers could help stratify patients likely to benefit and guide microbiome-directed treatment strategies, which is the central gap this review addresses.

Greater gut microbial diversity and enrichment of specific taxa, including Ruminococcaceae, Bifidobacterium, and Akkermansia, have been consistently associated with improved response to immune checkpoint inhibitors [1-3]. In contrast, enrichment of taxa, including Peptostreptococcaceae, Malassezia restricta, and Candida albicans, has been linked to poor therapeutic outcomes [4,5]. Members of the Lachnospiraceae family have been associated with both improved treatment response and reduced immune-related adverse events, potentially mediated by flagellin-related pathways that enhance antitumor immunity [6-8].

Metagenomic analyses demonstrate differences in microbial composition between responders and non-responders; for example, the Bacteroidota-to-Firmicutes ratio has been reported to be higher in responders [9]. Dietary factors also appear to influence microbiome composition and treatment outcomes, with distinct dietary patterns observed among patients with delayed response [10], and microbial signatures involving Bacteroides species have been implicated in predicting immune-related adverse events [11].

Collectively, these findings position the gut microbiome as a modulator of immunotherapy outcomes in melanoma. This review synthesizes current evidence on the relationship between gut microbiota composition and response to immune checkpoint inhibitors in melanoma, and evaluates the methodological quality of the underlying evidence base.