Photoinduced Synergism of Ferroptosis/Pyroptosis/Oncosis by an O2-Independent Photocatalyst for Enhanced Tumor Immunotherapy

Abstract

Due to O₂ dependence, hypoxia-induced apoptosis resistance, and immunosuppressive microenvironment, the effect of traditional photodynamic therapy toward hypoxic solid tumors is severely limited. Herein, we report an O₂-independent photocatalyst (EBSe) for tumor immunotherapy potentiation via synergism of near-infrared (NIR) light-induced ferroptosis/pyroptosis/oncosis. Simple Se and ethyl modifications on methylene blue (MB) endow EBSe with a remarkable phototoxicity enhancement (>2500 folds) and an excellent phototoxicity index (PI > 32,000) to 4T1 cells under hypoxia. EBSe exhibits self-adaptive photodynamic processes that generate enhanced type I/II ROS under normoxia and elevate carbon radical production under hypoxia. Interestingly, EBSe shows much higher cell uptake and undergoes photoinduced lysosomal-to-nucleus translocation, which activates ferroptosis, pyroptosis, and oncosis. The synergism of three nonapoptotic pathways potentiates antitumor immune responses in 4T1 tumor-bearing mice. This work offers a reliable strategy for developing powerful PSs to overcome the apoptosis resistance and immunosuppressive microenvironment of hypoxic tumors.