Bacterial vesicles from intratumoral L. salivarius enhance PD-1 blockade via FPR1-mediated macrophage polarization in gastric cancer.

The immunomodulatory function of the gastric microbiota in cancer is poorly understood, partly due to the stomach's acidic environment and limited microbial colonization. Here, by analyzing 68 paired human gastric cancer (GC) samples, we identify Ligilactobacillus salivarius as a commensal bacterium depleted in tumors but enriched in immune checkpoint blockade (ICB) responders. Oral administration of L. salivarius enhances anti-PD-1 efficacy in multiple GC mouse models by promoting pro-inflammatory macrophage activation. Mechanistically, bacterial extracellular vesicles (bEVs) derived from L. salivarius deliver 2,3-bisphosphoglycerate-dependent phosphoglycerate mutase (2,3-BdpM) to tumors, where it activates formyl peptide receptor 1 (FPR1) on macrophages, triggering mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling. Moreover, 2,3-BdpM augments the cytotoxic activity of chimeric antigen receptor (CAR)-Claudin18.2 macrophages in an FPR1-dependent manner. These findings describe a microbial-macrophage axis that enhances GC immunotherapy and highlights the translational potential of orally deliverable microbial adjuvants.