Abstract

Immune suppression is one of the primary obstacles in neoantigen immunotherapy because tumors can rapidly adapt by reducing MHC-I expression or antigen presentation. Here, we developed a novel immunotherapy strategy that combined vaccination of neoantigens with MICB α3 antigen, by using bacterial outer membrane vesicles (OMVs) as a versatile vector and adjuvant. This approach aims to simultaneously induce a neoantigen-specific cellular immune response and an anti-MICB α3 humoral immune response, to enhance the recognition and killing of tumor cells by immune cells. This strategy significantly improves the infiltration of neoantigen-specific T cells and NK cells, and reverses immunosuppression across various preclinical models. Mechanistically, ILC1s characterized by high GZMA/GZMB expression represent the primary subset accumulating within tumors and are responsible for enhancing antitumor immunity, which can induce Gasdermin D cleavage in tumor cells to initiate tumor pyroptosis for a cascade of cancer-immunity cycle. Overall, this study demonstrated that combined neoantigens and shared MICB α3 antigen for tumor vaccination enhances immune efficacy by eliciting ILC1s-mediated tumor pyroptosis and support the rationale and clinical translation for cancer immunotherapy. A bacterial outer membrane vesicle (OMV)-based dual-targeted vaccine was developed for combined delivery of personalized neoantigens and the shared MICB α3 domain to elicit synergistic antitumor immunity in solid tumors. The OMV vaccine platform simultaneously induced neoantigen-specific cellular immunity and anti-MICB α3 humoral immunity, overcoming tumor immune evasion mechanisms such as MICA/B shedding. The combined treatment activated a population of IL-15-armed ILC1s, which mediated GSDMD-dependent tumor pyroptosis and amplified the antitumor immune response.