An Electron Donor–Acceptor Structured Rhenium(I) Complex Photo‐Sensitizer Evokes Mutually Reinforcing "Closed‐Loop" Ferroptosis and Immunotherapy

Abstract

AbstractThe hypoxic microenvironment of solid tumors severely lowers the efficacy of oxygen‐dependent photodynamic therapy (PDT). The development of hypoxia‐tolerant photosensitizers for PDT is an urgent requirement. In this study, a novel rhenium complex (Re‐TTPY) to develop a “closed‐loop” therapy based on PDT‐induced ferroptosis and immune therapy is reported. Due to its electron donor–acceptor (D–A) structure, Re‐TTPY undergoes energy transfer and electron transfer processes under 550 nm light irradiation and displays hypoxia‐tolerant type I/II combined PDT capability, which can generate 1O2, O2−, and ·OH simultaneously. Further, the reactive oxygen species (ROSs) leads to the depletion of 1,4‐dihydronicotinamide adenine dinucleotide (NADH), glutathione peroxidase 4 (GPX4), and glutathione (GSH). As a result, ferroptosis occurs in cells, simultaneously triggers immunogenic cell death (ICD), and promotes the maturation of dendritic cells (DCs) and infiltration of T cells. The release of interferon‐γ (IFN‐γ) by CD8+ T cells downregulates the expression of GPX4, further enhancing the occurrence of ferroptosis, and thereby, forming a mutually reinforcing “closed‐loop” therapeutic approach.