Mitochondrial double-stranded RNA fuels pancreatic cancer growth via RIG-I/TLR3 inflammation
- Andrew T. Milcarek
- Minjeong Yeon
- Camilla Esposito
- Prerna Kulkarni
- Andrew V. Kossenkov
- Jozef Madzo
- Anneliese M. Faustino
- Hsin-Yao Tang
- Alessandra M. Storaci
- Alessandro Palleschi
- Marco Locatelli
- Valentina Vaira
- Mary V. Iacocca
- Andrea Ward
- Arvind Sabesan
- Nicholas J. Petrelli
- Michela Perego
- Dario C. Altieri
2026-04-28
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 NFκB 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.