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Mitochondrial reactive oxygen species promote cancer metastasis and tumor microenvironment immunosuppression through gasdermin D

  • 0Department of Oncology, Shanghai Fourth People's Hospital, Tongji University School of Medicine, Shanghai, 200434, China.
Cell Death Discovery +

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May 5, 2025

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May 5, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

Gasdermin D (GSDMD) drives breast cancer lung metastasis by promoting inflammation and immunosuppression. Inhibiting GSDMD reduces metastasis and enhances anti-tumor immunity, offering a potential therapeutic strategy.

Area Of Science

  • Immunology
  • Oncology
  • Cell Biology

Background

  • Gasdermin D (GSDMD) is crucial for pyroptosis, inflammation, and cell death.
  • The role of GSDMD in cancer metastasis, particularly breast cancer lung metastasis, remains largely unexplored.

Purpose Of The Study

  • To investigate the role of GSDMD in breast cancer metastasis.
  • To explore the underlying mechanisms of GSDMD-mediated metastasis.
  • To evaluate GSDMD as a potential therapeutic target for breast cancer lung metastasis.

Main Methods

  • Utilized a murine orthotopic 4T1 breast cancer model.
  • Assessed GSDMD levels in lung neutrophils during metastasis.
  • Investigated the correlation between cleaved GSDMD, mitochondrial ROS (mROS), and HMGB-1.
  • Examined the effect of mROS inhibition on GSDMD activation.
  • Studied GSDMD-induced neutrophil extracellular trap (NET) formation.
  • Administered GSDMD inhibitor LDC7559 and performed GSDMD knockout experiments.
  • Analyzed changes in myeloid-derived suppressor cells (MDSCs) and CD8+ T cells in the tumor microenvironment.

Main Results

  • GSDMD expression was significantly elevated in lung neutrophils of metastatic breast cancer models.
  • Cleaved GSDMD correlated positively with increased mROS and serum HMGB-1.
  • mROS inhibition suppressed GSDMD oligomerization and pore formation.
  • GSDMD activation enhanced NET formation.
  • GSDMD inhibition (LDC7559) or knockout significantly reduced lung metastasis.
  • GSDMD inhibition decreased MDSCs and increased CD8+ T cells in metastatic lungs.

Conclusions

  • Mitochondrial dysfunction-dependent GSDMD activation promotes breast cancer lung metastasis by inducing immunosuppression and NET formation.
  • GSDMD is a critical mediator of the pro-metastatic tumor microenvironment.
  • GSDMD inhibition represents a promising therapeutic strategy to mitigate breast cancer lung metastasis.

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