Smilax china L. Rhizome extract enhances anti-tumor immune responses by resetting M2-like macrophages and tumor-associated macrophages to M1-like via ERK1/2 signaling

Ethnopharmacological relevance: Smilax china L. is a traditional Chinese herb. Smilax china L. Rhizome (SCR) have historically been used in ethnomedicine for their anti-inflammatory, anti-tumor, and immunomodulatory properties.

Aim of the study: This study aimed to evaluate the anti-tumor efficacy of SCR in the MMTV-PyMT mouse mammary tumor model and elucidate its immunomodulatory mechanisms within the tumor microenvironment (TME).

Materials and methods: SCR was administered to MMTV-PyMT mice to assess its effects on tumor progression and metastasis. Immune cell profiling (M1/M2-like macrophages, CD8⁺ T cells) was conducted via flow cytometry. In vitro macrophage polarization assays under IL-4 stimulation and mechanistic studies (MAPK/ERK signaling) were performed using Western blot and pharmacological inhibitors. Diosgenin, a key SCR constituent, was identified and validated through phytochemical analysis and functional assays.

Results: SCR treatment significantly slowed primary tumor growth and reduced lung metastases. SCR induces a shift in macrophage polarization from immunosuppressive M2-like to proinflammatory M1-like and promotes increased CD8⁺ T cell infiltration. In vitro, SCR inhibited IL-4-induced M2 polarization and suppressed ERK1/2 phosphorylation, a critical node in the MAPK pathway. Diosgenin was identified as a pivotal bioactive compound contributing to SCR's anti-tumor and immunomodulatory effects.

Conclusions: These findings provide a theoretical basis for the potential clinical application of SCR in Cancer treatment, highlighting its critical role in remodeling the tumor immune microenvironment.

Breast cancer; ERK1/2 signaling pathway; Smilax china L.; Tumor microenvironment; Tumor-associated macrophage.