{
    "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-\u03baB signaling, thereby promoting tumor progression. While STING activation directly induced NF-\u03baB signaling, it also activated PKR-like endoplasmic reticulum kinase (PERK), which further amplified NF-\u03baB 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.",
    "authors": [
        {
            "affiliation": "Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Faculty of Biology and Medicine, University of Lausanne (UNIL), Lausanne 1011, Switzerland; Faculty of Biomedical Sciences, Universit\u00e0 della Svizzera Italiana, Lugano 6962, Switzerland.",
            "firstname": "Ping",
            "initials": "P",
            "lastname": "Lai"
        },
        {
            "affiliation": "Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Faculty of Biomedical Sciences, Universit\u00e0 della Svizzera Italiana, Lugano 6962, Switzerland.",
            "firstname": "Lei",
            "initials": "L",
            "lastname": "Liu"
        },
        {
            "affiliation": "Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Faculty of Biomedical Sciences, Universit\u00e0 della Svizzera Italiana, Lugano 6962, Switzerland.",
            "firstname": "Nicol\u00f2",
            "initials": "N",
            "lastname": "Bancaro"
        },
        {
            "affiliation": "Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Faculty of Biomedical Sciences, Universit\u00e0 della Svizzera Italiana, Lugano 6962, Switzerland.",
            "firstname": "Martina",
            "initials": "M",
            "lastname": "Troiani"
        },
        {
            "affiliation": "Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Faculty of Biomedical Sciences, Universit\u00e0 della Svizzera Italiana, Lugano 6962, Switzerland.",
            "firstname": "Bianca",
            "initials": "B",
            "lastname": "Cal\u00ec"
        },
        {
            "affiliation": "Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Faculty of Biomedical Sciences, Universit\u00e0 della Svizzera Italiana, Lugano 6962, Switzerland.",
            "firstname": "Yuxin",
            "initials": "Y",
            "lastname": "Li"
        },
        {
            "affiliation": "Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Faculty of Biology and Medicine, University of Lausanne (UNIL), Lausanne 1011, Switzerland.",
            "firstname": "Jingjing",
            "initials": "J",
            "lastname": "Chen"
        },
        {
            "affiliation": "Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Faculty of Biomedical Sciences, Universit\u00e0 della Svizzera Italiana, Lugano 6962, Switzerland.",
            "firstname": "Prafull Kumar",
            "initials": "PK",
            "lastname": "Singh"
        },
        {
            "affiliation": "Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Faculty of Biomedical Sciences, Universit\u00e0 della Svizzera Italiana, Lugano 6962, Switzerland.",
            "firstname": "Rydell Alvarez",
            "initials": "RA",
            "lastname": "Arzola"
        },
        {
            "affiliation": "Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Faculty of Biomedical Sciences, Universit\u00e0 della Svizzera Italiana, Lugano 6962, Switzerland.",
            "firstname": "Giuseppe",
            "initials": "G",
            "lastname": "Attanasio"
        },
        {
            "affiliation": "Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Faculty of Biomedical Sciences, Universit\u00e0 della Svizzera Italiana, Lugano 6962, Switzerland.",
            "firstname": "Nicol\u00f2",
            "initials": "N",
            "lastname": "Pernigoni"
        },
        {
            "affiliation": "Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Faculty of Biomedical Sciences, Universit\u00e0 della Svizzera Italiana, Lugano 6962, Switzerland.",
            "firstname": "Emiliano",
            "initials": "E",
            "lastname": "Pasquini"
        },
        {
            "affiliation": "Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Faculty of Biomedical Sciences, Universit\u00e0 della Svizzera Italiana, Lugano 6962, Switzerland.",
            "firstname": "Simone",
            "initials": "S",
            "lastname": "Mosole"
        },
        {
            "affiliation": "Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Faculty of Biomedical Sciences, Universit\u00e0 della Svizzera Italiana, Lugano 6962, Switzerland.",
            "firstname": "Andrea",
            "initials": "A",
            "lastname": "Rinaldi"
        },
        {
            "affiliation": "Faculty of Biomedical Sciences, Universit\u00e0 della Svizzera Italiana, Lugano 6962, Switzerland; Institute for Research in Biomedicine (IRB), Bellinzona 6500, Switzerland.",
            "firstname": "Jacopo",
            "initials": "J",
            "lastname": "Sgrignani"
        },
        {
            "affiliation": "Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu 610041, China.",
            "firstname": "Shi",
            "initials": "S",
            "lastname": "Qiu"
        },
        {
            "affiliation": "Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu 610041, China.",
            "firstname": "Pan",
            "initials": "P",
            "lastname": "Song"
        },
        {
            "affiliation": "Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Faculty of Biomedical Sciences, Universit\u00e0 della Svizzera Italiana, Lugano 6962, Switzerland.",
            "firstname": "Yingrui",
            "initials": "Y",
            "lastname": "Li"
        },
        {
            "affiliation": "Veneto Institute of Molecular Medicine (VIMM), Padova 35129, Italy; Department of Medicine, Universit\u00e0 degli Studi di Padova, Padova 35129, Italy.",
            "firstname": "Maria Andrea",
            "initials": "MA",
            "lastname": "Desbats"
        },
        {
            "affiliation": "Faculty of Biomedical Sciences, Universit\u00e0 della Svizzera Italiana, Lugano 6962, Switzerland; Laboratory of Cellular and Molecular Cardiology and Laboratory for Cardiovascular Theranostics, Cardiocentro Ticino Foundation, Lugano 6900, Switzerland.",
            "firstname": "Azucena Rend\u00f3n",
            "initials": "AR",
            "lastname": "\u00c1ngel"
        },
        {
            "affiliation": "Oncology Institute of Southern Switzerland (IOSI) Ente Ospedaliero Cantonale (EOC), Bellinzona 6500, Switzerland.",
            "firstname": "Ricardo Pereira",
            "initials": "RP",
            "lastname": "Mestre"
        },
        {
            "affiliation": "Faculty of Biomedical Sciences, Universit\u00e0 della Svizzera Italiana, Lugano 6962, Switzerland; Institute for Research in Biomedicine (IRB), Bellinzona 6500, Switzerland.",
            "firstname": "Andrea",
            "initials": "A",
            "lastname": "Cavalli"
        },
        {
            "affiliation": "Faculty of Biomedical Sciences, Universit\u00e0 della Svizzera Italiana, Lugano 6962, Switzerland; Laboratory of Cellular and Molecular Cardiology and Laboratory for Cardiovascular Theranostics, Cardiocentro Ticino Foundation, Lugano 6900, Switzerland.",
            "firstname": "Lucio",
            "initials": "L",
            "lastname": "Barile"
        },
        {
            "affiliation": "Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK.",
            "firstname": "Johann",
            "initials": "J",
            "lastname": "de Bono"
        },
        {
            "affiliation": "Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Faculty of Biomedical Sciences, Universit\u00e0 della Svizzera Italiana, Lugano 6962, Switzerland; Veneto Institute of Molecular Medicine (VIMM), Padova 35129, Italy; Department of Medicine, Universit\u00e0 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), Eidgen\u00f6ssische Technische Hochschule (ETH) Zurich, Zurich 8092, Switzerland. Electronic address: andrea.alimonti@ior.usi.ch.",
            "firstname": "Andrea",
            "initials": "A",
            "lastname": "Alimonti"
        }
    ],
    "conclusions": null,
    "copyrights": "Copyright \u00a9 2025 The Author(s). Published by Elsevier Inc. All rights reserved.",
    "doi": "10.1016/j.immuni.2025.03.005",
    "journal": "Immunity",
    "keywords": [
        "DAMP",
        "PMN-MDSCs",
        "cGAS-STING pathway",
        "immunosuppression",
        "innate immunity",
        "mtDNA",
        "senescence",
        "tumor microenvironment"
    ],
    "methods": null,
    "publication_date": "2025-04-10",
    "pubmed_id": "40203808",
    "results": null,
    "title": "Mitochondrial DNA released by senescent tumor cells enhances PMN-MDSC-driven immunosuppression through the cGAS-STING pathway.",
    "xml": "<Element 'PubmedArticle' at 0x788502e48ea0>"
}