Harnessing the Bacterial Membrane‐Derived Oral Vaccine to Potentiate Antitumor Immunity and Metabolic Control of T Cells

ABSTRACT The fluctuating gastrointestinal milieu and its restrictive epithelial barrier represent critical challenges for the design of oral cancer vaccines. Nevertheless, leveraging the gut microbiome as an interventional strategy has recently gained traction, especially in patients on immune checkpoint inhibitor (ICI) therapy. Here, microbial‐derived double‐layered membrane vesicles are developed as adjuvants and cell‐free carriers, fused with cell‐penetrating peptide‐modified antigens, and encapsulated in an alginate/chitosan‐microsystem to engineer oral vaccines. This design strategically harnesses the crosstalk between the gut microbiome and gut‐associated lymphoid tissues, driving dendritic cell maturation, plasma cell activation, and production of immune‐stimulatory cytokines within the mesenteric lymph nodes and lamina propria. In mouse prophylactic and therapeutic tumor models, the select Bifidobacterium bifidum ‐derived oral vaccine combined with anti‐PD1 treatment enhances cytotoxic antitumor responses, along with Th1‐, Th17‐immunity, leading to potent tumor suppression, prolonged survival, and long‐term protection against tumor rechallenge. Mechanistically, the vaccine promotes interferon‐γ‐producing T cells and antitumor efficacy with ICI therapy via the improved microbiota diversity and signaling metabolites, with an indole‐3‐acetic‐acid (3IAA) enriched diet profoundly shaping T‐cell recruitment and differentiation. Our findings uncover a tryptophan metabolite‐driven immune axis that amplifies the specific antitumor immune response, redefining oral vaccines as a powerful tool for cancer immunotherapy.