On‐Demand Autophagy Cascade Amplification Nanoparticles Precisely Enhanced Oxaliplatin‐Induced Cancer Immunotherapy
Xuhui Wang, Man Li, Kebai Ren, Chunyu Xia, Jianping Li, Qianwen Yu, Yue Qiu, Zhengze Lu, Yang Long, Zhirong Zhang, Qin He
Abstract
Chemoimmunotherapy-induced antitumor immune response is highly dependent on tumor autophagy. When tumor cells are treated with chemoimmunotherapy, timely overactivated autophagy can not only lead more tumor cells to death, but also participate in the endogenous antigen presentation and immune stimulators secretion of dying cells, thus plays a vital role. However, timely and accurately overactivated tumor autophagy during chemoimmunotherapy is of great difficulty. Here, an on-demand autophagy cascade amplification nanoparticle (ASN) is reported to boost oxaliplatin-induced cancer immunotherapy. ASN is prepared by self-assemble of autophagy-responsible C-TFG micelle and is followed by electrostatic binding of oxaliplatin prodrug (HA-OXA). After entering tumor cells, the HA-OXA shell of ASN first responds to the reduction microenvironment and releases oxaliplatin to trigger tumor immunogenic cell death and mildly stimulates tumor autophagy. Then, the exposed C-TFG micelle can sensitively respond to oxaliplatin-induced autophagy and release a powerful autophagy inducer STF-62247, which precisely transforms autophagy to "overactivated" condition, leading tumor cells to autophagic death and enhance subsequent tumor antigen processing of the dying cells. In CT26 tumor-bearing mice, ASN exhibits optimal immune stimulation and antitumor efficiency due to its on-demand autophagy induction ability.