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

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.