Dual-Pronged Light-Free Photodynamic Immunotherapy Enabled by a Chemiexcited Hydrogel

While singlet oxygen (¹O₂)-based therapies like photodynamic therapy (PDT) demonstrate clinical anticancer efficacy, their dependence on external light and substantial O₂ consumption significantly limits their broader application. To surmount these constraints, we develop a chemiexcited (light-independent) PDT platform by encapsulating bis[2,4,5-trichloro-6-(pentyloxycarbonyl) phenyl] oxalate (CPPO) and chlorin e6 (Ce6) within the 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(poly-ethyleneglycol)-2000] (ammonium salt) (DSPE-PEG₂₀₀₀-OMe) micelle (termed CCM). The CCM is then incorporated along with vitamin C (Vc) into a Ca²⁺-alginate hydrogel, forming a final product denoted as CCMVH. Following intratumoral injection of CCMVH, the sustained Vc release continuously elevates the tumoral H₂O₂ level. Subsequent reaction of H₂O₂ with CPPO generates chemical energy, activating Ce6 to produce ¹O₂ without light. More importantly, we employ hyperbaric oxygen (HBO) to sustain the high intratumoral O₂ level during chemiexcited PDT. The synergy between Vc-driven H₂O₂ generation and HBO-mediated O₂ supply creates a dual-pronged amplification effect that significantly enhances ¹O₂ production. In addition, this light-independent PDT induces marked immunogenic cell death, promotes the infiltration of antitumor immune cells, and reprograms the immunosuppressive tumor microenvironment, resulting in potent tumor inhibition. This work provides a facile strategy for overcoming the fundamental limitations of conventional PDT, offering a translatable approach for cancer immunotherapy.