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  3. mtDNA/RNA boosts radiation-induced abscopal effect via M1 macrophage polarization-promoted IFN-β-dependent inflammatory response

mtDNA/RNA boosts radiation-induced abscopal effect via M1 macrophage polarization-promoted IFN-β-dependent inflammatory response

  • Int Immunopharmacol. 2025 May 16:155:114673. doi: 10.1016/j.intimp.2025.114673.
Yuting Gao 1,  Boyi Yu 2,  Linjing Li 2,  Jiahao Zhang 3,  Ting Zhao 4,  Xianglong Feng 2,  Ryoichi Hirayama 5,  Cuixia Di 2,  Yanshan Zhang 6,  Yancheng Ye 6,  Yuan Li 7,  Qiang Li 8,  Xiaodong Jin 9
Affiliations

Affiliations

  • 1 Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China; School of Life Sciences, Northwest Normal University, Gansu Province, Lanzhou 730070, China.
  • 2 Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China; Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China; Lanzhou University, Lanzhou 730000, Gansu Province, China.
  • 4 Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China; Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000, China.
  • 5 National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan.
  • 6 Gansu Wuwei Tumor Hospital, Wuwei 733000, Gansu Province, China.
  • 7 School of Life Sciences, Northwest Normal University, Gansu Province, Lanzhou 730070, China. Electronic address: liyuan@nwnu.edu.cn.
  • 8 Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China; Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: liqiang@impcas.ac.cn.
  • 9 Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China; Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: jinxd@impcas.ac.cn.
PMID: 40245773 DOI: 10.1016/j.intimp.2025.114673
Abstract

The radiation-induced abscopal effect (RIAE) can suppress distal metastatic lesions and elicit a systemic anti-tumor response; however, the underlying mechanisms remain to be fully elucidated. Current research has shown that Autophagy promotes the production of IFN-β by regulating mitochondrial DNA (mtDNA), thereby contributing to the modulation of RIAE. Nevertheless, the downstream pathways through which IFN-β influences RIAE require further investigation. In this study, we observed accumulation of an abundance of mtDNA in the cytosol of mammary tumor cells following RT, along with the presence of mitochondrial RNA (mtRNA). These molecules activated the cGAS-STING and RIG-I-MAVS signaling pathways, respectively, thereby synergistically promoting the production of IFN-β and secretion into the extracellular matrix. Subsequently, IFN-β facilitated the polarization of macrophages in distant non-irradiated tumor microenvironment towards the M1 phenotype through activating STAT1. Furthermore, our findings indicate that high linear energy transfer (LET) carbon ions are significantly more effective in inducing the production of IFN-β and promoting macrophage polarization compared to low-LET X-rays. Thus, our findings provide insights into the intricate mechanisms by which mtDNA/RNA and IFN-β mediate RIAE, suggesting that IFN-β could be a promising target for provoking RT immunogenicity in patients with breast Cancer and high-LET radiation might effectively elicit RIAE.

Keywords

IFN-β; Macrophage; RIAE; mtDNA/RNA.

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