Chlorogenic acid promotes mtDNA leakage to enhance cGAS-STING induced anti-tumor immunity via ATF5-mtHSP70-TFAM system.

Mitochondrial targeting represents a promising antitumor strategy by modulating cell differentiation, metabolic reprogramming, and immune responses. While chlorogenic acid (CGA) has demonstrated the ability to induce tumor cell differentiation and enhance antitumor immunity, the involvement of mitochondrial regulation in these effects remains unclear. This study investigated whether CGA mediates antitumor immune effects through mitochondrial regulation, thereby providing a theoretical framework for natural product-based, mitochondria-targeted therapies. Our findings reveal that CGA inhibits the translocation of mitochondrial transcription factor A (TFAM) into the mitochondria and promotes mtDNA leakage by disrupting the ATF5-mtHSP70 signaling axis. The cytosolic leakage of mtDNA activates the cGAS/STING pathway, triggering the activation of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), which ultimately facilitates antitumor immunity. In a mouse model, ATF5 knockout enhances cGAS/STING signaling and subsequent immune responses, leading to tumor growth inhibition. These results highlight a novel role of CGA in regulating mitochondrial-associated proteins, positioning it as a potential therapeutic strategy for cancer via the mtDNA-cGAS-STING pathway.