Tumor-responsive cuproptosis nanoinducer realizing efficient PANoptosis for enhanced cancer immunotherapy
Kaiqing Yun, Xiaohong Yu, Shuang Liang, Qingling Wang, Ziyi Zhang, Yue Han, Yueyang Zhao, Yuxuan Peng, Lang Rao, Yong Cui, Zhaohui Wang
Abstract
Rationale:The induction of multiple forms of regulated cell death (RCD) presents a promising approach for antitumor immunotherapy.However, the heterogeneous tumor microenvironment (TME) limits the efficacy of single-mode RCD induction strategies.Methods: We engineered Elesclomol-Cu@PDPA nanoparticles (PEC NPs) designed to induce cuproptosis and subsequent PANoptosis.These NPs remain stable during circulation but rapidly dissociate in the acidic TME, releasing Cu 2+ and Elesclomol to trigger cuproptosis. Results:The cuproptosis induced by PEC NPs resulted in PANoptosis of tumor cells.This process stimulated immunogenic cell death and activated a systemic immune response by promoting immune cell infiltration and reprogramming the immunosuppressive TME.PEC NPs demonstrated potent tumor growth inhibition and exhibited a synergistic antitumor effect when combined with immune checkpoint blockade therapy.Conclusions: This study provides a robust strategy utilizing PEC NPs to induce efficient cuproptosis and PANoptosis for enhanced immunotherapy.It offers new insights into boosting tumor immunogenicity through the activation of multiple RCDs pathways.