Phloroglucinol suppresses esophageal squamous cell carcinoma metastasis by modulating TGF-β/SMAD2/3/SNAI2 signaling and macrophage-derived paracrine TGF-β

Abstract Esophageal squamous cell carcinoma (ESCC) is characterized by aggressive metastatic progression. Although Phloroglucinol (PhG), a clinically used natural polyphenolic compound, exhibits anti-tumor activity, whether it coordinately targets tumor cells and the tumor microenvironment during ESCC metastasis remains unclear. The present study demonstrated that PhG significantly inhibited ESCC cell migration and invasion in vitro and suppressed tumor metastasis in zebrafish and mouse models. Transcriptomic profiling and functional validation revealed that PhG attenuated TGF-β-induced SMAD2/3 phosphorylation and suppressed EMT-associated SNAI2 expression in ESCC cells, supporting the involvement of TGF-β/SMAD/SNAI2 signaling in its tumor cell-intrinsic anti-metastatic activity. Furthermore, in a macrophage–tumor cell conditioned-medium model, PhG attenuated tumor-conditioned macrophage-associated M2-like features, reduced macrophage-derived TGF-β secretion, and diminished the paracrine pro-migratory activity of macrophage-conditioned medium toward ESCC cells. Collectively, these findings demonstrate that PhG suppresses ESCC metastasis through coordinated regulation of tumor cell-intrinsic TGF-β/SMAD/SNAI2 signaling and macrophage-derived paracrine TGF-β signaling. These findings support the therapeutic potential of PhG in the treatment of metastatic ESCC.