2. Academic Validation
  3. Mitochondrial reactive oxygen species promote cancer metastasis and tumor microenvironment immunosuppression through gasdermin D

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

  • Cell Death Discov. 2025 May 6;11(1):219. doi: 10.1038/s41420-025-02516-7.
Naijun Miao # 1 2,  Zhengchun Kang # 3,  Zhuning Wang # 2,  Wenyan Yu # 1,  Ting Liu 4,  Ling-Zhijie Kong 1,  Ying Zheng 1,  Changli Ding 1,  Zhiyong Zhang 1,  Chen Zhong 5,  Qingliang Fang 6,  Kaichun Li 7
Affiliations

Affiliations

  • 1 Department of Oncology, Shanghai Fourth People's Hospital, Tongji University School of Medicine, Shanghai, 200434, China.
  • 2 Center for Immune-related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 3 Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
  • 4 Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 5 Department of Medical Oncology, The 960th Hospital of the PLA Joint Logistice Support Force, Jinan, 250031, Shandong, China. zhongchen0504@sina.com.
  • 6 Department of Radiation Oncology, LongHua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China. fangqingliang@shutcm.edu.cn.
  • 7 Department of Oncology, Shanghai Fourth People's Hospital, Tongji University School of Medicine, Shanghai, 200434, China. likaichun@tongji.edu.cn.
  • # Contributed equally.
PMID: 40324993 DOI: 10.1038/s41420-025-02516-7
Abstract

Although recent research has established that gasdermin D (GSDMD), a factor that drives Pyroptosis, is essential for cell death and inflammation, its involvement in Cancer metastasis has yet to be elucidated. In this study, GSDMD was significantly increased in lung neutrophils at the metastatic stage from a murine orthotropic 4T1 breast Cancer model. Moreover, the N terminal domain from cleaved GSDMD exhibited a positive correlation with increased mitochondrial Reactive Oxygen Species (mROS) and serum high mobility group box 1 (HMGB-1) levels. Mechanistically, mROS inhibition significantly suppressed GSDMD-N oligomerization and pore formation. In addition, the activation of GSDMD significantly enhanced the formation of neutrophil extracellular traps (NETs) following treatment with Cathepsin C. Within a murine orthotopic breast Cancer model using 4T1 cell line, the inhibition of GSDMD through the application of LDC7559 significantly attenuated the metastatic spread of breast Cancer to the lung. In addition, knockout of GSDMD reduced lung metastasis in E0771 intravenous injection murine model. Furthermore, inhibition of GSDMD reduced the number of myeloid derived suppressor cells (MDSC) in the metastatic lung of breast Cancer mouse model, while concurrently increasing both the percentage and total cell count of CD8+ T cells, suggesting that mitochondrial dysfunction-dependent GSDMD activation promotes tumor microenvironment immunosuppression and NETs. GSDMD represents a promising therapeutic target for mitigating the metastatic progression of breast Cancer to the lung.

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