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Circulating mitochondrial DNA promotes M2 polarization of tumor associated macrophages and HCC resistance to

Qi Yang1,2,3, Mengmeng Cui2,3,4,5, Jiaxin Wang2,3,4,5

  • 1School of Life Sciences, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China.

Cell Death & Disease
|March 4, 2025
PubMed

Insights

Sorafenib resistance in liver cancer is linked to mitochondrial DNA (mtDNA) released into the tumor microenvironment. This mtDNA promotes M2 macrophage polarization, hindering treatment effectiveness.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Mitochondrial damage-associated molecular patterns (DAMPs) regulate inflammation in diseases.
  • The role of mitochondrial DAMPs in the tumor microenvironment (TME) is not fully understood.
  • Tumor-associated macrophages (TAMs), particularly M2-type, are implicated in cancer progression and treatment resistance.

Purpose of the Study:

  • To investigate the role of mitochondrial DAMPs in hepatocellular carcinoma (HCC) resistance to sorafenib.
  • To elucidate the mechanism by which mitochondrial DAMPs influence the TME and TAM polarization.
  • To identify potential strategies to overcome sorafenib resistance in HCC.

Main Methods:

  • Assessed plasma cell-free mitochondrial DNA (mtDNA) levels in sorafenib-resistant HCC mouse models.
  • Investigated the effect of sorafenib on mitochondrial dysfunction and mtDNA release in HCC cells.
  • Utilized DNase I to digest mtDNA and clodronate liposomes to deplete macrophages in vivo.
  • Blocked Toll-like receptor 9 (TLR9) signaling to assess its impact on sorafenib efficacy.

Main Results:

  • Sorafenib-resistant HCC mice showed increased plasma cell-free mtDNA.
  • Sorafenib treatment induced mitochondrial dysfunction and mtDNA release, activating TLR9 signaling in macrophages.
  • M2 TAM polarization was observed in sorafenib-resistant HCC, driven by mtDNA.
  • Digesting mtDNA or depleting macrophages reduced M2 TAM infiltration, inhibited HCC growth, and sensitized tumors to sorafenib.
  • Blocking TLR9 activation enhanced sorafenib's therapeutic effect.

Conclusions:

  • Sorafenib treatment releases mtDNA into the HCC TME, promoting M2 TAM polarization via TLR9 activation.
  • This mtDNA-mediated reprogramming of TAMs contributes to sorafenib resistance in HCC.
  • Targeting mtDNA or TLR9 signaling presents a promising strategy to improve sorafenib efficacy and overcome resistance in HCC.

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