Mitochondrial DNA abundance is a determinant of immunogenic cell death in cancer.

In KRAS-mutant cancer cells, MEK inhibition drives cytosolic mtDNA release, but PRKN-mediated mitophagy limits it, shaping whether death becomes immunogenic rather than apoptotic.

• Why it matters: The field lacks clear determinants of when mitochondrial stress yields innate immune activation versus apoptosis in cancer, limiting rational immunotherapy design.
• What they did: A pharmacological screen showed MEKi induces mtDNA efflux in KRAS-mutant cells; blocking mitophagy sustained mtDNA release and amplified cGAS-STING signaling, linked to PRKN restraining MOMP.
• The result: In preclinical models, combined MEK and mitophagy inhibition increased dendritic cell activation and promoted CD8+ T cell antitumor immunity, while PRKN expression negatively correlated with immune infiltration in human cancers.

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