Ferroptosis Photoinduced by New Cyclometalated Iridium(III) Complexes and Its Synergism with Apoptosis in Tumor Cell Inhibition

Abstract Limited therapeutic efficacy to hypoxic and refractory solid tumors has hindered the practical application of photodynamic therapy (PDT). Two new benzothiophenylisoquinoline (btiq)‐derived cyclometalated Ir III complexes, IrL1 and MitoIrL2 , were constructed as potent photosensitizers, with the latter being designed for mitochondria accumulation. Both complexes demonstrated a type I PDT process and caused photoinduced ferroptosis in tumor cells under hypoxia. This ferroptosis featured lipid peroxide accumulation, mitochondria shrinkage, down‐regulation of glutathione peroxidase 4 (GPX4), and ferrostatin‐1 (Fer‐1)‐inhibited cell death. Upon photoirradiation under hypoxia, mitochondria targeting MitoIrL2 caused mitochondria membrane potential (MMP) collapse, ATP production suppression, and induced cell apoptosis. The synergetic effect of ferroptosis and apoptosis causes MitoIrL2 to outperform IrL1 in inhibiting the growth of MCF‐7, PANC‐1, MDA‐MB‐231 cells and multicellular spheroids. This study demonstrates the first example of ferroptosis induced by photosensitizing Ir III complexes. Moreover, the synergism of ferroptosis and apoptosis provides a promising approach for combating hypoxic solid tumors through type I PDT processes.