Amount of mitochondrial DNA influences immune-triggered cancer cell death

High expression of the cGAS-STING pathway and abundant mitochondrial DNA (mtDNA) are features of KRAS-mutant cancers.

• Mitochondrial stress can lead to apoptosis or immune activation in cancer cells.
• In KRAS-mutant cancer cells, a MEK inhibitor effectively triggers mtDNA release into the cytosol.
• PRKN-mediated mitophagy limits mtDNA release by removing damaged mitochondria.
• Inhibition of mitophagy enhances mtDNA efflux and amplifies cGAS-STING signaling.
• The balance of mtDNA and cytochrome c release determines whether immunogenic cell death or apoptosis occurs.
• In preclinical models, combined targeting of MEK and mitophagy promotes dendritic cell activation and CD8⁺ T cell immunity.

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