Bacterial Foreignization Nanosystem Elicits Multi-Phenotypic T Cells for Antitumor Immunity

T lymphocytes are pivotal targets in clinical cancer immunotherapy; however, tumor cells frequently evade the T-cell attacks by altering the intrinsic immunogenicity manifested as adjuvanticity, antigenicity, and reactogenicity. Here, a bacterial outer membrane vesicle (OMVs)-based nanosystem is presented to elicit robust T-cell responses by reshaping tumor immunogenicity. OMVs are engineered with vesicular stomatitis virus G-protein that facilitates the fusion of OMVs with tumor cells, leading to tumor “foreignization” and adjuvanticity augment. Consequently, the innate immune system is mobilized to sense the foreignized tumor cells and present the whole-cell tumor antigens, significantly improving the tumor antigenicity and priming multi-phenotypic T cells, including both pathogen-specific and tumor-specific T cells. Meanwhile, the tumor reactogenicity is reinvigorated through direct cytoplasmic delivery of siPD-L1 during the fusion, amplifying T cells-mediated cytotoxicity. In murine models, this foreignization strategy potentiates adaptive immunity and induces durable immune memory, thus effectively suppressing bilateral and metastatic tumors, demonstrating its therapeutic potential in comprehensively reprogramming tumor immunogenicity to fight cancer.