Breast cancer (Dove Medical Press) · 2025
Differential TGF-β1/SMAD4 Signaling Regulates PMN-MDSC Differentiation and Reshapes the Immune Microenvironment in Breast Cancer.
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Cao Jie, Qiao Enqi, Shao Hui, Wang Chunlei, Xia Manzhi, Qin Bo
Аннотация
PURPOSE: Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) exert strong immunosuppressive effects and are associated with poor prognosis in breast cancer. However, the mechanism underlying their differentiation remains unclear. Here, we aimed to elucidate how transforming growth factor-β1 (TGF-β1)/SMAD4 signaling regulates PMN-MDSC differentiation and modulates the breast cancer immune microenvironment.
METHODS: We analyzed neutrophil subpopulation heterogeneity in breast cancer tissues using single-cell RNA sequencing combined with spatial transcriptomics (GSE176078 dataset). A 4T1 mouse breast cancer metastasis model was established, and tumor progression was tracked via in vivo fluorescence imaging. Colony formation and differentiation outcomes following Tgfb1 overexpression or knockdown were assessed in spleen-derived hematopoietic stem cells using flow cytometry. Gene expression profiles and signaling pathways were characterized using RNA sequencing and Western blotting.
RESULTS: Neutrophil subpopulations in breast cancer tissues exhibited significant heterogeneity, particularly the N3 subset, which showed enhanced intracellular communication and regulatory potential. Tgfb1 was significantly upregulated along the neutrophil developmental trajectory in both spleen tissue and serum of breast cancer mice. In normal mice, the number of metastatic foci significantly correlated with neutrophil proportions. Tgfb1 overexpression promoted PMN-MDSC differentiation, colony formation, and SMAD4 upregulation in normal mice but exerted opposite effects in tumor-bearing mice.
CONCLUSION: Our findings implicate TGF-β1/SMAD4 signaling in the differential regulation of PMN-MDSC differentiation in breast cancer models. The TGF-β1 pathway represents a potential therapeutic target for modulating the immune microenvironment in breast cancer, although further validation in clinical settings is required to determine therapeutic efficacy.
METHODS: We analyzed neutrophil subpopulation heterogeneity in breast cancer tissues using single-cell RNA sequencing combined with spatial transcriptomics (GSE176078 dataset). A 4T1 mouse breast cancer metastasis model was established, and tumor progression was tracked via in vivo fluorescence imaging. Colony formation and differentiation outcomes following Tgfb1 overexpression or knockdown were assessed in spleen-derived hematopoietic stem cells using flow cytometry. Gene expression profiles and signaling pathways were characterized using RNA sequencing and Western blotting.
RESULTS: Neutrophil subpopulations in breast cancer tissues exhibited significant heterogeneity, particularly the N3 subset, which showed enhanced intracellular communication and regulatory potential. Tgfb1 was significantly upregulated along the neutrophil developmental trajectory in both spleen tissue and serum of breast cancer mice. In normal mice, the number of metastatic foci significantly correlated with neutrophil proportions. Tgfb1 overexpression promoted PMN-MDSC differentiation, colony formation, and SMAD4 upregulation in normal mice but exerted opposite effects in tumor-bearing mice.
CONCLUSION: Our findings implicate TGF-β1/SMAD4 signaling in the differential regulation of PMN-MDSC differentiation in breast cancer models. The TGF-β1 pathway represents a potential therapeutic target for modulating the immune microenvironment in breast cancer, although further validation in clinical settings is required to determine therapeutic efficacy.