Strain-level genetic heterogeneity and colonization dynamics drive microbiome therapeutic efficacy

Fecal microbiota transplantation (FMT) has shown immunotherapeutic promise, yet its efficacy in non-small-cell lung cancer (NSCLC) remains unclear. We demonstrate that FMT improves anti-PD-1 efficacy and progression-free survival in a single-arm trial of advanced PD-L1-negative NSCLC. Analyzing over 2,000 metagenomes from diverse disease cohorts and healthy controls via a high-resolution strain-tracking framework, we reveal that phylogenetically distinct strains within identical species exert opposing therapeutic effects, resolving prior inconsistencies. We identify conserved ecological principles where engraftment relies on species-intrinsic metabolic and immune evasion traits. Crucially, successful colonization by specific beneficial strain variants correlates with positive clinical outcomes. Finally, we identify 38 priority species with robust engraftment potential and significant heterogeneity as candidates for precision therapeutics. These findings establish a strain-function-efficacy paradigm, elucidating the mechanistic basis of variable outcomes and guiding next-generation microbiome drug development.