Simultaneous activation of apoptosis and cGAS-STING pathway with a mitochondria-targeted dehydrocholic acid compound for enhanced hepatocellular carcinoma chemoimmunotherapy.

The activation of the cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) pathway triggered by mitochondrial DNA (mtDNA) represents a highly promising strategy in tumor immunotherapy. Herein, we report a mitochondria-targeting small-molecule compound (3c), which contains dehydrocholic acid and acts as an activator of the cGAS-STING pathway in hepatocellular carcinoma (HCC). Specifically, 3c could target the mitochondria of HepG2 cells, regulate mitochondrial function, generate a large amount of reactive oxygen species (ROS), open the mitochondrial permeability transition pore (mPTP), and promote the release of mtDNA into the cytoplasm to further trigger the cGAS-STING pathway. Treatment of immunocompetent C57BL/6 mice bearing Hepa1-6 tumors with 3c activates their immune system, inducing an antitumor CD8⁺ T cell response and dendritic cell (DC) maturation; this process elicits a potent antitumor immune response by activating the cGAS-STING signaling pathway in HCC cells. Moreover, 3c can also induce apoptosis in HepG2 cells, which may be attributed to oxidative stress caused by elevated ROS levels. With the dual actions of cGAS-STING pathway activation and chemotherapy against HCC, 3c has great potential as an antitumor agent, and further serves as a preclinical proof-of-concept for chemoimmunotherapy. To the best of our knowledge, 3c is one of the few mitochondria-targeting small-molecule compounds that can induce an immunomodulatory response by activating the cGAS-STING pathway. Overall, we present a novel example of cGAS-STING pathway activation mediated by a mitochondria-targeted dehydrocholic acid-derived compound, which may provide an innovative strategy for designing chemoimmunotherapies for HCC.