Intratumoral Fusogenic Outer Membrane Vesicles Enhance Antitumor Immunity Through Tumor MHC‐I Upregulation and Tumor Bacterization

Cold tumors evade APC and T‐cell surveillance through low immunogenicity, defective antigen presentation, and immunosuppressive tumor microenvironments. We uncovered a non‐canonical function of bacterial outer membrane vesicles (OMVs), whereby OMVs activated the TLR4–NF‐κB–NLRC5 axis to induce tumor MHC I upregulation, thereby restoring tumor visibility to T cells. To further eliminate tumor invisibility to APCs, we reported a bacteria‐inspired strategy that drives APCs to perceive tumor cells as bacteria. By fusing OMVs with fusogenic liposomes, we constructed fusogenic OMVs (FOs) that anchor bacterial membrane components onto tumor surfaces, thereby functionally “bacterizing” tumor cells. This modification markedly increased APC recruitment and effectively reprogrammed APC perception from silent tumor clearance to active microbial‐like immune surveillance. Consequently, APCs exhibited enhanced phagocytic uptake of bacterized tumors, enabling efficient cross‐presentation of the tumor‐antigen repertoires to T cells. Concurrently, OMVs upregulated MHC I expression on tumor cells, which strengthened effector T cell recognition and cytotoxicity toward tumors. Furthermore, by loading 3‐bromopyruvate into the vesicles, we endowed the system with metabolic reprogramming capability, characterized by glycolysis suppression and lactate depletion. Together, the synergistic immune–metabolic modulation resulted in durable suppression of tumor progression following intratumoral administration, offering a bacterization‐inspired nanoplatform to overcome key immunological barriers in immune‐cold tumors. Tumor bacterization by fusogenic outer membrane vesicles enhances microbial‐like recognition of tumor cells while activating the TLR4–NF‐κB–NLRC5 axis to upregulate MHC class I expression. By simultaneously strengthening APC sensing and T‐cell recognition, this strategy breaks tumor immune invisibility and promotes more effective antitumor immune surveillance.