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Updated: May 15, 2025

Techniques to Induce and Quantify Cellular Senescence
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Techniques to Induce and Quantify Cellular Senescence

Published on: May 1, 2017

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

Ping Lai1, Lei Liu2, Nicolò Bancaro2

  • 1Institute 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.

Immunity
|April 9, 2025
PubMed

Insights

Senescent cells release mitochondrial DNA (mtDNA) packaged in vesicles, which enhances immunosuppressive myeloid cells in tumors. Inhibiting mtDNA release via VDAC channels improved chemotherapy efficacy in prostate cancer models.

Area of Science:

  • Immunology
  • Cellular Biology
  • Cancer Research

Background:

  • Cellular senescence is linked to mitochondrial dysfunction.
  • The role of extracellular mitochondrial DNA (mtDNA) in innate immunity and tumor progression is not fully understood.

Purpose of the Study:

  • To investigate the release of mtDNA from senescent cells.
  • To determine the impact of extracellular mtDNA on the tumor microenvironment and innate immunity.
  • To explore the therapeutic potential of targeting mtDNA release.

Main Methods:

  • Primary and therapy-induced senescent cells were analyzed for mtDNA release.
  • Extracellular vesicles containing mtDNA were characterized.
  • The transfer of mtDNA to polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) was studied.
  • cGAS-STING-NF-κB and PERK signaling pathways were investigated.
  • Voltage-dependent anion channels (VDACs) were targeted pharmacologically in prostate cancer mouse models.

Main Results:

  • Senescent cells actively release mtDNA into the extracellular environment, packaged within extracellular vesicles.
  • Extracellular mtDNA is transferred to PMN-MDSCs, enhancing their immunosuppressive activity via cGAS-STING-NF-κB and PERK signaling.
  • Pharmacological inhibition of VDAC reduced extracellular mtDNA, reversed PMN-MDSC immunosuppression, and improved chemotherapy efficacy in preclinical models.

Conclusions:

  • Extracellular mtDNA released by senescent cells promotes tumor progression by enhancing PMN-MDSC immunosuppression.
  • Targeting VDAC-mediated mtDNA release offers a potential strategy to reprogram the tumor microenvironment.
  • Inhibiting mtDNA release may improve therapeutic outcomes for cancer patients undergoing chemotherapy.
Keywords:
DAMPPMN-MDSCscGAS-STING pathwayimmunosuppressioninnate immunitymtDNAsenescencetumor microenvironment

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