Restoring Zinc Homeostasis via a Bimetallic Nanozyme to Amplify Ferroptosis and Antitumor Immunity for Prostate Cancer Treatment.

Abstract

Prostate cancer therapy is hindered by treatment resistance and an immunosuppressive microenvironment. To address this, we developed an innovative bimetallic nanozyme, Fe/Zn-CNZ@LOx@PEG, that integrates catalytic activity with metabolic and immune modulation. This nanoplatform executes a novel "metabolic-immuno" co-regulation strategy. Its Fe-Zn catalytic sites drive a lactate-fueled cascade reaction within the acidic tumor milieu, generating a burst of cytotoxic hydroxyl radicals. Simultaneously, released zinc ions rectify tumor zinc deficiency, disrupting cellular metabolism and promoting ferroptosis-an iron-dependent cell death-through glutathione depletion and lipid peroxidation. This ferroptotic cell death, in turn, acts as a potent trigger for immunogenic cell death (ICD), stimulating dendritic cell maturation and cytotoxic T cell infiltration to reverse immunosuppression. Consequently, Fe/Zn-CNZ@LOx@PEG demonstrates potent tumor suppression and effectively enhances the efficacy of anti-PD-1 therapy in a prostate cancer mouse model. This work presents a catalytic nanoreactor that co-regulates metabolism and immunity, offering a robust and synergistic strategy for the ferroptosis-immunotherapy of advanced cancers.