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Peer-reviewedCC BY 4.0Cell Death Discovery

Mitophagy-dependent mitochondrial DNA release links ionizing radiation to immunogenic cell death in pancreatic cancer

  • Chenghao Li1
  • Yanxian Ren2
  • Yong Chen3
  • Huaying Yu4
  • Jintao Cui4
  • Fei Wang4
  • Jin Li4
  • Ao Sun4
  • Heng Zhou2,3,4
4 affiliations
  1. 1School of Traditional Chinese Medicine, Faculty of Medicine, Yangzhou University, Yangzhou, 225009 China
  2. 2Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, 730000 China
  3. 3Department of Radio-Chemotherapy, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225002 China
  4. 4School of Basic Medical Sciences & School of Public Health, Faculty of Medicine, Yangzhou University, Yangzhou, 225009 China
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Abstract

Ionizing radiation (IR) elicits both cytotoxic and immunomodulatory effects, yet the precise link between mitochondrial remodeling and immunogenic cell death (ICD) remains elusive. Here, we report that IR triggers robust mitophagy in pancreatic cancer cells, marked by mitochondrial damage, Parkin/BNIP3 upregulation, and increased autophagic flux. In parallel, IR induces key hallmarks of ICD, including calreticulin exposure, HMGB1 translocation, and the release of ATP and IFN-β. Notably, genetic or pharmacological inhibition of mitophagy attenuated this immunogenic profile, whereas mitophagy induction amplified it. We further demonstrate that mitophagy triggers the cytosolic release of mitochondrial DNA (mtDNA) to activate immune signaling, which can be reversed by blocking mtDNA replication. In murine models, Parkin overexpression enhanced mitophagy and ICD marker expression, leading to reduced tumor burden and prolonged survival following irradiation. Collectively, our findings indicate that mtDNA leakage downstream of mitophagy links mitochondrial remodeling to radiation-induced ICD, suggesting that modulation of mitochondrial dynamics may represent a strategy to enhance both radiosensitivity and the immunogenic potential of radiotherapy in pancreatic cancer.

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Cite

BibTeXRIS
BibTeX
@article{li2026mitophagydependent,
  title = {{Mitophagy-dependent mitochondrial DNA release links ionizing radiation to immunogenic cell death in pancreatic cancer}},
  author = {Chenghao Li and Yanxian Ren and Yong Chen and Huaying Yu and Jintao Cui and Fei Wang and Jin Li and Ao Sun and Heng Zhou},
  journal = {Cell Death Discovery},
  year = {2026},
  month = jul,
  doi = {10.1038/s41420-026-03269-7},
  url = {https://doi.org/10.1038/s41420-026-03269-7},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Mitophagy-dependent mitochondrial DNA release links ionizing radiation to immunogenic cell death in pancreatic cancer
AU  - Chenghao Li
AU  - Yanxian Ren
AU  - Yong Chen
AU  - Huaying Yu
AU  - Jintao Cui
AU  - Fei Wang
AU  - Jin Li
AU  - Ao Sun
AU  - Heng Zhou
PY  - 2026
DA  - 2026/07/01
JO  - Cell Death Discovery
DO  - 10.1038/s41420-026-03269-7
UR  - https://doi.org/10.1038/s41420-026-03269-7
AB  - Ionizing radiation (IR) elicits both cytotoxic and immunomodulatory effects, yet the precise link between mitochondrial remodeling and immunogenic cell death (ICD) remains elusive. Here, we report that IR triggers robust mitophagy in pancreatic cancer cells, marked by mitochondrial damage, Parkin/BNIP3 upregulation, and increased autophagic flux. In parallel, IR induces key hallmarks of ICD, including calreticulin exposure, HMGB1 translocation, and the release of ATP and IFN-β. Notably, genetic or pharmacological inhibition of mitophagy attenuated this immunogenic profile, whereas mitophagy induction amplified it. We further demonstrate that mitophagy triggers the cytosolic release of mitochondrial DNA (mtDNA) to activate immune signaling, which can be reversed by blocking mtDNA replication. In murine models, Parkin overexpression enhanced mitophagy and ICD marker expression, leading to reduced tumor burden and prolonged survival following irradiation. Collectively, our findings indicate that mtDNA leakage downstream of mitophagy links mitochondrial remodeling to radiation-induced ICD, suggesting that modulation of mitochondrial dynamics may represent a strategy to enhance both radiosensitivity and the immunogenic potential of radiotherapy in pancreatic cancer.
SN  - 2058-7716
ER  -