Salvia miltiorrhiza Bunge aqueous extract inhibits lung metastasis of breast cancer by inhibiting recruitment of M2-like macrophages via CCL2-STAT3 axis

Med Oncol. 2025 Jun 27;42(8):286. doi: 10.1007/s12032-025-02840-z.

Abstract

The purpose of this study was to evaluate the therapeutic effect of Salvia miltiorrhiza Bunge on breast cancer (BC) metastasis and explore its possible mechanism. The anti-tumor lung metastasis effect of S. miltiorrhiza Bunge aqueous extract (Sme) and tumor-associated macrophages (TAMs) infiltration was observed in 4T1 spontaneous metastasis models. Wound healing and transwell assays assessed the anti-mobility effects of Sme in 4T1 cells and TAMs. Finally, the therapeutic mechanisms of Sme on BC lung metastasis were explored through Hematoxylin-Eosin Staining(HE), enzyme-linked immunosorbent assay (ELISA), network pharmacology and molecular docking, immunohistochemistry (IHC) staining, quantitative real-time PCR (qRT-PCR), and western blotting (WB). Mechanically, Sme was able to reduce the ability of BC cells to recruit macrophages and reduce the release of C-C motif ligand 2 (CCL2). Additionally, WB results show Sme inhibited the p-STAT3 and suppressed the epithelial-mesenchymal transition of the tumor (p < 0.05). In conclusion, S. miltiorrhiza Bunge may lower the incidence of BC. Sme blocks BC cell-macrophage interactions by regulating the CCL2-STAT3 axis, reducing BC cell migration. These findings may form the basis of new treatments for BC progression. Sme blocks BC cell-macrophage interactions by uniquely regulating the CCL2-STAT3 axis. Our research results provide strong pharmacological evidence for the clinical treatment of lung metastasis of BC with S. miltiorrhiza Bunge.

Keywords: Salvia miltiorrhiza Bunge aqueous extract; Breast cancer lung metastases; C-C motif ligand 2; Tumor-associated macrophages.

MeSH terms

  • Animals
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / metabolism
  • Breast Neoplasms* / pathology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Chemokine CCL2* / metabolism
  • Female
  • Humans
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / metabolism
  • Lung Neoplasms* / prevention & control
  • Lung Neoplasms* / secondary
  • Macrophages* / drug effects
  • Macrophages* / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Plant Extracts* / pharmacology
  • STAT3 Transcription Factor* / metabolism
  • Salvia miltiorrhiza* / chemistry
  • Signal Transduction / drug effects
  • Tumor-Associated Macrophages* / drug effects

Substances

  • STAT3 Transcription Factor
  • Chemokine CCL2
  • Plant Extracts
  • Stat3 protein, mouse
  • Ccl2 protein, mouse
  • STAT3 protein, human