A microbiota-derived bile acid overcomes antibiotic-induced hyporesponsiveness to immune checkpoint therapy by enhancing CD8+ T cell antitumor immunity

Abstract

Gut microbiota are critical determinants of effective immune checkpoint therapy (ICT), yet the microbial mediators and host mechanisms that enhance antitumor immunity remain poorly understood. Here, we identify the microbiota-derived bile acid taurodeoxycholic acid (TDCA) as a metabolite associated with immune checkpoint therapy (ICT) response. TDCA administration alone is sufficient to overcome antibiotic-induced ICT hyporesponsiveness across multiple murine tumor models. Mechanistically, TDCA directly enhances CD8 T cell-mediated antitumor immunity, increasing cytotoxicity. These effects required signaling through the bile acid receptor TGR5. Together, these findings reveal TDCA as a gut microbial metabolite that restores ICT efficacy after antibiotic disruption by directly augmenting CD8 T cell anti-tumor activity. This work supports metabolite replacement as a therapeutic strategy to mitigate antibiotic-associated loss of cancer immunotherapy response. SignificanceTDCA is a microbiota-derived metabolite that restores immune checkpoint therapy efficacy after antibiotic disruption by directly enhancing CD8 T-cell-mediated anti-tumor immunity through bile acid receptor TGR5 signaling. Our findings suggest that supplementation with defined microbial metabolites can mitigate antibiotic-associated loss of immunotherapy response without requiring broader microbiome reconstitution.