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  3. Mitochondrial DNA released by senescent tumor cells enhances PMN-MDSC-driven immunosuppression through the cGAS-STING pathway

Mitochondrial DNA released by senescent tumor cells enhances PMN-MDSC-driven immunosuppression through the cGAS-STING pathway

  • Immunity. 2025 Apr 8;58(4):811-825.e7. doi: 10.1016/j.immuni.2025.03.005.
Ping Lai 1,  Lei Liu 2,  Nicolò Bancaro 2,  Martina Troiani 2,  Bianca Calì 2,  Yuxin Li 2,  Jingjing Chen 3,  Prafull Kumar Singh 2,  Rydell Alvarez Arzola 2,  Giuseppe Attanasio 2,  Nicolò Pernigoni 2,  Emiliano Pasquini 2,  Simone Mosole 2,  Andrea Rinaldi 2,  Jacopo Sgrignani 4,  Shi Qiu 5,  Pan Song 5,  Yingrui Li 2,  Maria Andrea Desbats 6,  Azucena Rendón Ángel 7,  Ricardo Pereira Mestre 8,  Andrea Cavalli 4,  Lucio Barile 7,  Johann de Bono 9,  Andrea Alimonti 10
Affiliations

Affiliations

  • 1 Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Faculty of Biology and Medicine, University of Lausanne (UNIL), Lausanne 1011, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano 6962, Switzerland.
  • 2 Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano 6962, Switzerland.
  • 3 Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Faculty of Biology and Medicine, University of Lausanne (UNIL), Lausanne 1011, Switzerland.
  • 4 Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano 6962, Switzerland; Institute for Research in Biomedicine (IRB), Bellinzona 6500, Switzerland.
  • 5 Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu 610041, China.
  • 6 Veneto Institute of Molecular Medicine (VIMM), Padova 35129, Italy; Department of Medicine, Università degli Studi di Padova, Padova 35129, Italy.
  • 7 Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano 6962, Switzerland; Laboratory of Cellular and Molecular Cardiology and Laboratory for Cardiovascular Theranostics, Cardiocentro Ticino Foundation, Lugano 6900, Switzerland.
  • 8 Oncology Institute of Southern Switzerland (IOSI) Ente Ospedaliero Cantonale (EOC), Bellinzona 6500, Switzerland.
  • 9 Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK.
  • 10 Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano 6962, Switzerland; Veneto Institute of Molecular Medicine (VIMM), Padova 35129, Italy; Department of Medicine, Università degli Studi di Padova, Padova 35129, Italy; Oncology Institute of Southern Switzerland (IOSI) Ente Ospedaliero Cantonale (EOC), Bellinzona 6500, Switzerland; Department of Health Sciences and Technology (D-HEST), Eidgenössische Technische Hochschule (ETH) Zurich, Zurich 8092, Switzerland. Electronic address: andrea.alimonti@ior.usi.ch.
PMID: 40203808 DOI: 10.1016/j.immuni.2025.03.005
Abstract

Mitochondrial dysfunction is a hallmark of cellular senescence. Here, we investigated whether senescent cells release mitochondrial (mt)DNA into the extracellular space and its impact on innate immunity. We found that both primary senescent cells and tumor cells undergoing therapy-induced senescence actively released mtDNA into the extracellular environment. mtDNA released by senescent cells was packaged within extracellular vesicles and selectively transferred to polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in the tumor microenvironment. Upon uptake, extracellular mtDNA enhanced the immunosuppressive activity of PMN-MDSCs via cGAS-STING-NF-κB signaling, thereby promoting tumor progression. While STING activation directly induced NF-κB signaling, it also activated PKR-like endoplasmic reticulum kinase (PERK), which further amplified NF-κB activity, in PMN-MDSCs. mtDNA release from senescent cells was mediated by voltage-dependent anion channels (VDACs), and pharmacological inhibition of VDAC reduced extracellular mtDNA levels, reversed PMN-MDSC-driven immunosuppression, and enhanced chemotherapy efficacy in prostate Cancer mouse models. These findings suggest that targeting mtDNA release could reprogram the immunosuppressive tumor microenvironment, improving therapeutic outcomes for chemotherapy-treated patients.

Keywords

DAMP; PMN-MDSCs; cGAS-STING pathway; immunosuppression; innate immunity; mtDNA; senescence; tumor microenvironment.

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