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Stress-induced expansion of myeloid-derived suppressor cells (MDSCs) and subsequent immune remodeling play critical roles, with aberrant myeloid differentiation of hematopoietic stem and progenitor cells (HSPCs) serving as a major source of MDSCs. This study investigates whether epicatechin gallate (ECG) suppresses stress-driven TNBC growth and lung metastasis by regulating HSPC myeloid differentiation. Methods: A mouse model of chronic unpredictable mild stress (CUMS) followed by 4T1 tumor implantation was used to evaluate the anti-tumor effects of ECG. CETSA-WB, molecular docking, HSPC differentiation assays, and MDSC functional validation assays, along with immunohistochemistry, immunofluorescence, and flow cytometry, were performed to elucidate how ECG modulates glucocorticoid (GC)\/glucocorticoid receptor (GR) signaling and HSPC differentiation. Results: ECG dose-dependently alleviated depressive-like behaviors, reduced serum corticosterone (Cort), and inhibited tumor growth and lung metastasis. Notably, ECG decreased lung metastatic foci by 76.9% relative to the CUMS group. Mechanistically, chronic stress activated GR and induced its nuclear translocation in HSPCs, promoting aberrant HSPC-to-MDSC differentiation. ECG directly bound GR, blocked its nuclear translocation, and suppressed the myeloid differentiation of HSPCs into MDSCs, which was accompanied by downregulation of S100A8\/A9, fibronectin, and MMP-2, as well as increased CD8+ T cell infiltration. Supernatants from ECG-pretreated and differentiated HSPCs reversed Cort-induced epithelial\u2013mesenchymal transition (EMT) in 4T1 cells. Conclusions: ECG acts as a natural GR signaling blocker that directly targets GR to block chronic stress-driven abnormal myeloid differentiation of HSPCs, thereby remodeling the pulmonary immune microenvironment, suppressing EMT, and reducing breast cancer lung metastasis. These findings identify ECG as a promising GR signaling blocker and a potential adjuvant therapy for cancer patients under high-stress conditions.<\/jats:p>","DOI":"10.3390\/ph19081211","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T01:43:27Z","timestamp":1785721407000},"page":"1211","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Epicatechin Gallate Blocks GC\/GR Signaling to Suppress Stress-Induced Myeloid Differentiation of HSPCs and Subsequent TNBC Metastasis"],"prefix":"10.3390","volume":"19","author":[{"given":"Meiling","family":"Ma","sequence":"first","affiliation":[{"name":"State Key Laboratory of Traditional Chinese Medicine Syndrome, Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China"},{"name":"State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"},{"name":"Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9630-1657","authenticated-orcid":false,"given":"Guanzhi","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Traditional Chinese Medicine Syndrome, Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China"},{"name":"State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"},{"name":"Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Physiotherapy, School of Acupuncture and Rehabilitation Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangxian","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Traditional Chinese Medicine Syndrome, Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanjun","family":"Shen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Traditional Chinese Medicine Syndrome, Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhitao","family":"Guo","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, The Fifth Clinical College, Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuezhen","family":"Li","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, The Fifth Clinical College, Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifeng","family":"Zheng","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengqi","family":"Wang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Pan","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, 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