Diselenide‐Based Dual‐Responsive Prodrug as Pyroptosis Inducer Potentiates Cancer Immunotherapy

Abstract Pyroptosis is demonstrated to trigger antitumor immunity and represents a promising new strategy to potentiate cancer immunotherapy. The number of potent pyroptosis inducers, however, is limited and without tumor‐targeting capability, which inevitably causes damage in normal tissues. Herein, a small molecular prodrug of paclitaxel‐oxaliplatin is rationally synthesized, which can be covalently self‐assembled with diselenide‐containing cross‐linking (Dse11), producing a diselenide nanoprodrug (DSe@POC) to induce pyroptosis for the first time. The diselenide bonds within DSe@POC can be split by high glutathione in the tumor microenvironment (TME) and reactive oxygen species induced by photodynamic therapy, thus possessing excellent TME on‐target effects. Additionally, DSe@POC is able to elicit intense pyroptosis to remodel the immunostimulated TME and trigger a robust immune response. Furthermore, combined α PD‐1 therapy effectively inhibits the growth of remote tumors through the abscopal effect, amplifies a long‐term immune memory response to reject rechallenged tumors, and prolongs survival. Collectively, DSe@POC, as the first TME dual‐responsive diselenide‐based pyroptosis inducer, will open up an attractive approach for cancer immunotherapy.