Neoantigens and shared MICB α3 antigen dual-targeted vaccine generates potent antitumor immunity.

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.