A Nanoplatform to Amplify Apoptosis-to-Pyroptosis Immunotherapy via Immunomodulation of Myeloid-Derived Suppressor Cells

Pyroptosis is a programmed cell death to enhance immunogenicity of tumor cells, but pyroptosis-based immunotherapy is limited due to the immune escape involving myeloid-derived suppressor cells (MDSCs). Therefore, designing a nanoplatform to not only trigger apoptosis-pyroptosis transformation but also combat the MDSC-based immune escape is of great significance. As a proof-of-concept study, here, we designed a metal organic framework (MOF)-based nanoplatform to tailor the pyroptosis immunotherapy through disrupting the MDSC-mediated immunosuppression. By pH-responsive zeolitic imidazolate framework-8 (ZIF-8) modified with hyaluronic acid (HA), the chemotherapeutic drug mitoxantrone (MIT) and DNA demethylating agent hydralazine (HYD) were successfully co-encapsulated into ZIF-8 for achieving (M+H)@ZIF/HA nanoparticles. This nanoplatform demonstrated a powerful apoptosis-to-pyroptosis transformation with a potent disruption of MDSC-mediated T cell paralysis via reducing immunosuppressive methylglyoxal by HYD. Overall, our two-pronged nanoplatform (M+H)@ZIF/HA can switch the cold tumor into an arsenal of antigens that stimulate robust immunological responses, while suppressing immune escape, collectively triggering vigorous cytotoxic T cell responses with remarkable tumor elimination and building a long-term immune memory response against metastasis.