Activation of the cGAS-STING pathway by a mitochondrial DNA-targeted emissive rhodium(iii) metallointercalator

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon (STING) pathway is a key mediator of innate immunity involved in cancer development and treatment. The roles of mitochondrial DNA (mtDNA) in cancer immunotherapy have gradually emerged. Herein, we report a highly emissive rhodium(iii) complex (Rh-Mito) as the mtDNA intercalator. Rh-Mito can specifically bind to mtDNA to cause the cytoplasmic release of mtDNA fragments to activate the cGAS-STING pathway. Moreover, Rh-Mito activates the mitochondrial retrograde signaling by disturbing the key metabolites involved in epigenetic modifications, which alters the nuclear genome methylation landscape to influence the expression of genes related to immune signaling pathways. Finally, we demonstrate that ferritin-encapsulated Rh-Mito elicits potent anticancer activities and evokes intense immune responses in vivo by intravenous injection. Overall, we report for the first time that small molecules targeting mtDNA can activate the cGAS-STING pathway, which gives insights into the development of biomacromolecule-targeted immunotherapeutic agents.

Automated summary

We report a highly emissive rhodium(III) complex (Rh-Mito) as the mtDNA intercalator that specifically binds to mtDNA, causing cytoplasmic release of mtDNA fragments to activate the cGAS-STING pathway. Rh-Mito also activates mitochondrial retrograde signaling and alters nuclear genome methylation landscape to influence genes related to immune signaling pathways. Furthermore, ferritin-encapsulated Rh-Mito elicits potent anticancer activities and immune responses in vivo. This study provides insights into the development of biomacromolecule-targeted immunotherapeutic agents.