Self‐Destructive Copper Carriers Induce Pyroptosis and Cuproptosis for Efficient Tumor Immunotherapy Against Dormant and Recurrent Tumors

Abstract

Activating the strong immune system is a key initiative to counteract dormant tumors and prevent recurrence. Herein, self-destructive and multienzymatically active copper-quinone-GOx nanoparticles (abbreviated as CQG NPs) have been designed to induce harmonious and balanced pyroptosis and cuproptosis using the "Tai Chi mindset" to awaken the immune response for suppressing dormant and recurrent tumors. This cleverly designed material can disrupt the antioxidant defense mechanism of tumor cells by inhibiting the nuclear factor-erythroid 2-related factor 2 (NRF2)-quinone oxidoreductase 1 (NQO1) signaling pathway. Furthermore, combined with its excellent multienzyme activity, it activates NOD-like receptor protein 3 (NLRP3)-mediated pyroptosis. Meanwhile, cuproptosis can be triggered by copper ions released from the self-destructive disintegration of CQG NPs and the sensitivity of cancer cells to cuproptosis is enhanced through the depletion of endogenous copper chelators via the Michael addition reaction between glutathione (GSH) and quinone ligand, oxygen production from catalase-like reaction, and starvation-induced glucose deficiency. More importantly, CQG NPs-induced pyroptosis and cuproptosis can promote immunosuppressive tumor microenvironment (TME) remodeling, enhance the infiltration of immune cells into the tumor, and activate robust systemic immunity. Collectively, this study provides a new strategy to resist tumor dormancy, prevent tumor recurrence, and improve the clinical prognosis of tumors.