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.