Diselenide‐Based Dual‐Responsive Prodrug as Pyroptosis Inducer Potentiates Cancer Immunotherapy
Shu‐Cheng Wan, Meng‐Jie Ye, Qi‐Chao Yang, Tian Zhang, Meng‐Jie Zhang, Xianbin Ma, Jiming Xu, Shuo Wang, Zhi‐Zhong Wu, Leilei Yang, Xue‐Meng Shen, Zhigang Xu, Zhi‐Jun Sun
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 αPD-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.