Mitochondrial DNA released by senescent tumor cells enhances PMN-MDSC-driven immunosuppression through the cGAS-STING pathway
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.
Authors
- Simone Mosole (ORCID: https://orcid.org/0000-0002-0765-1426)
- Martina Troiani
- Emiliano Pasquini (ORCID: https://orcid.org/0000-0001-9158-9671)
- Nicolò Bancaro (ORCID: https://orcid.org/0000-0003-2102-6421)
- Bianca Calì (ORCID: https://orcid.org/0000-0002-9090-9992)
- Yingrui Li (ORCID: https://orcid.org/0000-0003-1429-7127)
- Rydell Alvarez Arzola
- Nicolò Pernigoni (ORCID: https://orcid.org/0000-0001-5115-8447)
- Ricardo Pereira Mestre (ORCID: https://orcid.org/0000-0002-3123-3697)
- Andrea Rinaldi (ORCID: https://orcid.org/0000-0003-3234-0563)
- Lucio Barile (ORCID: https://orcid.org/0000-0002-5827-0439)
- Shi Qiu (ORCID: https://orcid.org/0000-0001-7749-4123)
- Jacopo Sgrignani (ORCID: https://orcid.org/0000-0002-8633-1032)
- María Andrea Desbats (ORCID: https://orcid.org/0000-0003-2643-0650)
- Giuseppe Attanasio
- Azucena Rendón Ángel
- Johann Sebastian De Bono (ORCID: https://orcid.org/0000-0002-2034-595X)
- Andrea Alimonti (ORCID: https://orcid.org/0000-0002-9362-2313)
- Jingjing Chen (ORCID: https://orcid.org/0000-0001-6994-0074)
- Andrea Cavalli (ORCID: https://orcid.org/0000-0003-4063-4502)
- Yuxin Li (ORCID: https://orcid.org/0000-0001-9739-9860)
- Lei Liu (ORCID: https://orcid.org/0000-0001-6290-8602)
- Ping Lai (ORCID: https://orcid.org/0009-0003-6959-6375)
- Prafull Kumar Singh (ORCID: https://orcid.org/0000-0002-0529-9748)
- Pan Song
Institutions
- Royal Marsden NHS Foundation Trust (GB)
- Sichuan University (CN)
- Veneto Institute of Molecular Medicine (IT)
- West China Hospital of Sichuan University (CN)
- Swiss Institute for Regenerative Medicine (CH)
- Ente Ospedaliero Cantonale (CH)
- Institute of Oncology Research (CH)
- Università della Svizzera italiana (CH)
- University of Lausanne (CH)
Publication Details
- Journal
- Immunity
- Published
- 2025-04-01
- DOI
- https://doi.org/10.1016/j.immuni.2025.03.005
- Citations
- 72
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 57.42
Funders
- Prostate Cancer Foundation
- Novartis Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Novartis Stiftung für Medizinisch-Biologische Forschung
- Associazione Italiana per la Ricerca sul Cancro
- Swiss Cancer Research Foundation
- Fondation ISREC
- European Research Council