Targeted PhotoredoxSystem under a Hypoxic Environmentto Evoke Photodynamic Immunotherapy

Abstract Conventional oxygen dependent type-II photodynamic therapy (PDT) was significantly constrained by the hypoxic tumor microenvironment. Type-I photosensitizers (PSs) produce oxygen radicals through the electron transfer (ET) pathway and are less oxygen dependent. However, no proven design strategy for generic Type-I PSs has been clarified. In this work, type-I PS BDP-Ir-bpt has been successfully synthesized, with the modification of triplet state energy via ligand upgradation. Under hypoxia with 630 nm irradiation with PS BDP-Ir-bpt, the intracellular photoredox system was disrupted and intracellular O2–• and •OH were significantly produced. Oxygen radicals further ruptured the lysosomal membrane, releasing cathepsin B and inducing GSDMD-mediated pyroptosis. Subsequently, the innate immune responses were evoked, as observed in an in vivo mouse prophylactic model. This work not only provided a biocompatible photosensitizer to relieve the hypoxic microenvironment and initiate photodynamic immunotherapy but also demonstrated the importance of the rational structural design for cancer therapy.