Mitochondrial double-stranded RNA fuels pancreatic cancer growth via RIG-I/TLR3 inflammation
Menée à partir de l'analyse d'échantillons de tissus pancréatiques prélevés sur des patients atteints d'un adénocarcinome canalaire du pancréas, cette étude met en évidence un mécanisme par lequel l'ARN double brin des mitochondries favorise la croissance tumorale via un processus inflammatoire induit par les récepteurs RIG-I et TLR3
Mitochondria activate inflammation and innate immunity to protect against infections, but the role in cancer is unknown. Here, we report that patients with pancreatic ductal adenocarcinoma (PDAC) with reduced levels of the mitochondrial scaffold, Mic60, or inner mitochondrial membrane protein, exhibit increased inflammation, high NF
κB activity and production of TNFα. This is mediated by double-stranded RNA (dsRNA) released from structurally defective, Mic60-low mitochondria, which engages TLR3/RIG-I sensing, activates NFκB gene expression and reprograms transcriptional and signaling networks to promote PDAC proliferation. Preclinical targeting of mitochondrial dsRNA signaling triggers rapid cell death and inhibition of tumor growth, selectively in Mic60-knockdown PDAC, without overt toxicity, in vivo. Therefore, dsRNA released from defective mitochondria generates protumorigenic inflammation and provides an actionable therapeutic target in selected PDAC patients.
Proceedings of the National Academy of Sciences , article en libre accès, 2026