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.