Ecological and Functional Stratification of the Stool Microbiome Predicts Response to Immune Checkpoint Inhibitors...

Despite the recognized role of the gut microbiome in modulating immune checkpoint inhibitor efficacy, the ecological principles governing this relationship remain elusive. Moving beyond cataloging specific bacteria, we investigated whether general ecosystem properties determine clinical outcome. Through genome-resolved metagenomic analysis, we constructed a comprehensive catalog from 951 stool metagenomes and subsequently analyzed a curated subset of 624 samples from 11 multicancer cohorts, with melanoma (72.7%, n = 456) and other cancer types collectively accounting for 27.3% (n = 171), including gastrointestinal, non-small-cell lung, breast, ovarian, and other types. Our catalog comprises 3,816 operational genomic units and reveals the key ecological determinants of immune checkpoint inhibitor response. Clinical benefit was associated with gut ecosystems dominated by prevalent, autochthonous taxa. Indeed, the population frequency of a taxon was a positive predictor of its favorable outcome association. Functionally, responder-associated microbes were enriched in genomic capacity for complex carbohydrate metabolism, including specialized mucin degradation and amino acid biosynthesis. In contrast, nonresponse was characterized by enrichment of low-prevalence, exogenous oral and food-derived bacteria and enriched for replication-associated pathways. Our results support an ecological interpretation of the "Anna Karenina principle" in microbiomes: response is linked to a stable, functionally coherent microbial community, whereas nonresponse represents a destabilized state with high individual variability. This reframes the search for biomarkers from individual taxa to the assessment of ecosystem stability and functional coherence, providing a foundation for microbiome-targeted strategies to improve cancer immunotherapy outcomes.