Integration of Donor Microbiota Following FMT Predicts Anti–PD-1 Response in Melanoma

Fecal microbiota transplantation (FMT) has shown promise improving anti–PD-1 therapy in melanoma, but the underlying microbial features remain poorly defined. We performed strain-resolved metagenomic analysis of three clinical trials and found therapeutic benefit was linked to successful integration of donor microbiota, rather than increased diversity or engraftment of specific species. Responders acquired more donor-derived strains, exhibited greater post-FMT similarity to their donor, and maintained a more stable microbial community. Non-responders showed greater shifts in taxonomic composition and estimated microbial load relative to baseline, and increased abundance of pathogen-associated secretion system genes. In responders, microbial functions involved in community-level metabolism and communication, including the phosphotransferase system and quorum sensing, were more prominent. Finally, tumor-infiltrating immune profiles tracked with clinical outcomes and microbiome changes. Together these findings highlight that distinct patterns of microbiome restructuring, including stable community transitions and enriched functional capacity, are associated with anti–PD-1 response following FMT.