Metal-Free Photocatalyst Photo-oxidizes NADPH to Trigger Pyropstosis and Disulfidptosis for Photocatalytic Therapy of Hypoxia Tumor

Given the role of redox homeostasis in tumor cells for maintaining various biological processes and cellular responses, depleting NADPH to disrupt this balance may serve as an effective antitumor strategy. In this study, a metal-free photocatalyst (PZZI) was designed and synthesized to induce disulfidptosis and pyroptosis by photo-oxidizing NADPH, thereby disturbing redox homeostasis for the photocatalytic treatment of hypoxic tumors. Upon light irradiation, PZZI promotes the photo-oxidation of NADPH and disrupts redox equilibrium. This process results in cystine accumulation and glutathione depletion, triggering disulfidptosis. Additionally, PZZI preferentially accumulates within the endoplasmic reticulum, induces ER stress, and activates Caspase-1-dependent pyroptosis. Tumor cells undergoing disulfidptosis and pyroptosis elicit robust immune responses by promoting immune cell infiltration and reprogramming the immunosuppressive tumor microenvironment. This work presents a novel approach to induce disulfidptosis and pyroptosis through NADPH photo-oxidation and disruption of redox homeostasis, offering a promising strategy for the photocatalytic treatment of tumors.