Gut microbial glycolipid engages Galectin-9 to modulate dendritic cell antitumor function

Abstract

The gut microbiome influences responses to immune checkpoint blockade, yet the molecular mechanisms by which commensal-derived molecules engage checkpoint circuitry remain poorly understood. Here, we identify a dual-mechanism pathway through which glycoconjugates of Bacteroides ovatus, an anaerobic gram-negative symbiont, regulate the Galectin-9 (Gal-9)-TIM-3 immune checkpoint axis in dendritic cells (DCs). We show that B. ovatus glycolipids induced Gal-9 expression in DCs through TLR4-TRIF-type I interferon signaling, while structurally distinct B. ovatus glycans competitively inhibited Gal-9 binding to TIM-3 and other checkpoint ligands, directly altering lectin binding kinetics. Together, these mechanisms reprogram DC transcriptional responses to commensal glycolipids, alter interferondriven antigen presentation programs, and destabilize TIM-3 on type 1 conventional DCs in vivo. This checkpoint remodeling reduces tumor burden and sensitizes tumors to aPDL1 therapy. These findings define commensal glycoconjugates as regulators of a lectin-mediated DC checkpoint pathway and establish a molecular basis for microbiome-informed strategies to improve cancer immunotherapy.