Abstract

Generally, autophagy/mitophagy, as a highly conserved lysosomal-based catabolic pathway, compromises the photodynamic therapy (PDT) efficiency by increasing the adaptation of tumor cells toward reactive oxygen species (ROS)-triggered protein damages and mitochondrial destruction. On the other hand, excessively activated autophagy/mitophagy cascades can provoke autophagic cell death and promote the endogenous antigens release of dying cells, thus playing a vital role in initiating the antitumor immune responses. To harness the exquisite immunomodulating effect of pro-death autophagy/mitophagy, we rationally constructed a MnO 2 shell-coated multifunctional porphyrinic metal–organic framework (MOF) to load carbonyl cyanide 3-chlorophenylhydrazone (CCCP). The wrapped MnO 2 shell could not only prevent premature release of CCCP during blood circulation but also conquer tumor hypoxia by catalyzing the decomposition of intratumoral H 2 O 2 . After entering tumor cells, the MnO 2 shell could scavenge over-expressed glutathione (GSH), resulting in burst CCCP release and GSH-depletion/O 2 -generation enhanced PDT. More importantly, the released CCCP acts as a mitochondrial uncoupler can elicit mitochondrial depolarization and mitophagy , which could significantly boost the autophagy/mitophagy levels generated during PDT and consequently convert the pro-survival autophagy/mitophagy to pro-death, leading tumor cells to autophagic and immunogenic cell death. In vivo results reveal that the CCCP synergistic PDT could induce excessive immunostimulatory autophagy/mitophagy associated with T-cell responses and immunological memory , leading to complete ablation of primary tumors and prevention of tumor recurrence and lung metastasis. The effectiveness of this strategy may highlight the pro-death role and immunomodulating effect of autophagy/mitophagy in cancer therapy, providing a novel yet versatile avenue to enhance the efficacy of cancer treatments.