Epicatechin Gallate Blocks GC/GR Signaling to Suppress Stress-Induced Myeloid Differentiation of HSPCs and Subsequent TNBC Metastasis

Background: Chronic psychological stress drives metastasis in triple-negative breast cancer (TNBC), yet the underlying mechanisms remain poorly understood and effective interventions are lacking. 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–mesenchymal 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.