Photoinduction\nof Ferroptosis and cGAS-STING Activation\nby a H<sub>2</sub>S‑Responsive Iridium(III) Complex for Cancer-Specific\nTherapy

Triggering\nferroptosis represents a promising anticancer\ntherapeutic\nstrategy, but the development of a selective ferroptosis inducer for\ncancer-specific therapy remains a great challenge. Herein, a H<sub>2</sub>S-responsive iridium(III) complex <b>NA-Ir</b> has been\nwell-designed as a ferroptosis inducer. <b>NA-Ir</b> could selectively\nlight up H<sub>2</sub>S-rich cancer cells, primarily localize in mitochondria,\nintercalate into mitochondrial DNA (mtDNA), and induce mtDNA damage,\nexhibiting higher anticancer activity under light irradiation. Mechanistic\nstudies showed that <b>NA-Ir</b>-mediated PDT triggered lipid\nperoxidation and glutathione peroxidase 4 downregulation through ROS\nproduction and GSH depletion, resulting in ferroptosis through multiple\npathways. Moreover, the intense mtDNA damage can activate the cyclic\nGMP–AMP synthase-stimulator of the interferon gene (cGAS-STING)\npathway, leading to ferritinophagy and further ferroptosis. RNA-sequencing\nanalysis showed that <b>NA-Ir</b>-mediated PDT mainly affects\nthe expression of genes related to ferroptosis, autophagy, and cancer\nimmunity. This study demonstrates the first cancer-specific example\nwith ferroptosis and cGAS-STING activation, which provides a new strategy\nfor multimodal synergistic therapy.