Mitoxantrone Combined with Engineered TRAIL‐Nanovesicles for Enhanced Cancer Immunotherapy Via Converting Apoptosis into Pyroptosis

Abstract Pyroptosis, a highly inflammatory form of programmed cell death, has emerged as a promising target for cancer immunotherapy. However, in the context of pyroptosis execution, while both caspase‐3 and GSDME are essential, it is noteworthy that GSDME is frequently under‐expressed in cold tumors. To overcome this limitation, engineered cellular nanovesicles (NVs) presenting TRAIL on their membranes (NV TRAIL ) are developed to trigger the upregulation of cleaved caspase‐3. When strategically combined with the chemotherapeutic agent mitoxantrone (MTO), known for its ability to enhance GSDME expression, MTO@NV TRAIL can convert cancer cells from apoptosis into pyroptosis, inhibit the tumor growth and metastasis successfully in primary tumor. The microparticles released by pyroptotic tumor cells also exhibited certain cytotoxicity against other tumor cells. In addition, tumor cells exposed to the combination treatment of MTO@NV TRAIL in vitro have also demonstrated potential utility as a novel form of vaccine for cancer immunotherapy. Flow analysis of the tumor microenvironment and draining lymph nodes reveals an increased proportion of matured dendritic cells and activation of T cells. In summary, the research provided a reference and alternative approach to induce cancer pyroptosis for clinical antitumor therapy based on engineered cellular nanovesicles and chemotherapy.