Photoinduction of Ferroptosis and cGAS-STING Activation by a H2S-Responsive Iridium(III) Complex for Cancer-Specific Therapy

Triggering Ferroptosis represents a promising Anticancer therapeutic strategy, but the development of a selective Ferroptosis inducer for cancer-specific therapy remains a great challenge. Herein, a H₂S-responsive iridium(III) complex NA-Ir has been well-designed as a Ferroptosis inducer. NA-Ir could selectively light up H₂S-rich Cancer cells, primarily localize in mitochondria, intercalate into mitochondrial DNA (mtDNA), and induce mtDNA damage, exhibiting higher Anticancer activity under light irradiation. Mechanistic studies showed that NA-Ir-mediated PDT triggered lipid peroxidation and Glutathione Peroxidase 4 downregulation through ROS production and GSH depletion, resulting in Ferroptosis through multiple pathways. Moreover, the intense mtDNA damage can activate the cyclic GMP-AMP synthase-stimulator of the interferon gene (cGAS-STING) pathway, leading to ferritinophagy and further Ferroptosis. RNA-sequencing analysis showed that NA-Ir-mediated PDT mainly affects the expression of genes related to Ferroptosis, Autophagy, and Cancer immunity. This study demonstrates the first cancer-specific example with Ferroptosis and cGAS-STING activation, which provides a new strategy for multimodal synergistic therapy.