Chemotherapeutics-enabled apoptosis-pyroptosis switch to trigger adaptive and innate immunity for metastatic breast cancer immunotherapy

Abstract

Pyroptosis-inducing chemotherapeutics hold promise for activating both adaptive and innate immunity in breast cancer immunotherapy. However, their practical efficacy is often limited by inadequate expression of pyroptosis-executed gasdermin and insufficient transfer of tumor-derived DNA. In this work, our findings indicated that the epigenetic drug of decitabine (DEC) can increase the gasdermin E (GSDME) level in breast cancer cells, while the DNA-damaging chemotherapeutic drug of 7-ethyl-10-hydroxycamptothecin (SN38) can activate caspase-3 and cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) pathway. Based on these discoveries, a glutathione (GSH)-responsive nanoplatform equipped with PD-L1 blockade peptide (PD-L1 pep) is further fabricated for targeting delivery of these chemotherapeutic combination to breast cancer cells. Interestingly, the apoptosis-pyroptosis switch (denoted as PL@SD) not only enables the cascade activation of caspase-3 and GSDME to induce an apoptosis-pyroptosis transition, but also accelerates the release of tumor-derived DNA through the pore-formation to elicit the cGAS-STING activity. Concurrently, PL@SD elevates dendritic cell maturation, cytotoxic T lymphocyte infiltration, natural killer cell recruitment and long-term immunological memory effect to boost adaptive and innate immunity, thus synergistically suppressing primary breast cancer, distant lung metastases and tumor rechallenge. Overall, this study presents an elaborate strategy for apoptosis-pyroptosis transition and cGAS-STING activation, which might provide a new insight to expand the applications of the existing therapeutic drugs for tumor immunotherapy.