Lactobacillus salivarius potentiates gastrointestinal cancer immunotherapy through its metabolite chenodeoxycholic acid.

Immune checkpoint inhibitor therapy has improved gastrointestinal (GI) cancer management; however, many patients exhibit resistance. Although gut microbiota influences immunotherapeutic responses, the underlying mechanisms remain unclear. Metagenomic analysis of 278 GI cancer patients reveals that Lactobacillus salivarius (L. salivarius) is enriched in responders and enhances anti-PD-1 efficacy in syngeneic tumor models by increasing the infiltration of antitumor M1-like macrophages and CD8+ T cells and enhancing CD8+ T cell effector function. L. salivarius-associated chenodeoxycholic acid (CDCA) is identified as a functional metabolite. CDCA recapitulates the antitumor effects of L. salivarius and significantly improves anti-PD-1 efficacy in vivo, an effect attenuated by depleting macrophages or CD8+ T cells. Mechanistically, CDCA-induced reactive oxygen species triggers immunogenic cell death in tumor cells and polarizes macrophages toward antitumor M1 phenotype, activating CD8+ T cell antitumor immunity. These findings identify L. salivarius and its associated metabolite CDCA as a promising adjuvant for potentiating immunotherapy in GI cancers.