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 Cu²⁺ 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.