Tumor-responsive cuproptosis nanoinducer realizing efficient PANoptosis for enhanced cancer immunotherapy

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.