GuBenPeiYuan Formula Inhibits Lung Cancer Metastasis by Suppressing Myeloid-Derived Suppressor Cells and Related Immune Cells.

Background: Lung cancer remains the leading cause of cancer-related morbidity and mortality all over the world, with high rates of locoregional recurrence and distant metastasis even after curative-intent surgical resection. The mechanisms of the tumor microenvironment's role in supporting metastasis through the formation of pre-metastatic niches are crucial areas of investigation.

Methods: Lung metastasis models were established by injecting Lewis lung cancer cells (LLCs) into the tail vein of 20 specific pathogen free (SPF)-grade male C57BL/6 mice. The mice were divided into 4 groups: control (physiological saline), GuBenPeiYuan (GBPY) medium-dose (25 g/kg), GBPY high-dose (50 g/kg), all administered by gavage, and gemcitabine (50 mg/kg, administered by intraperitoneal injection on days 1, 4, 7, 10, and 13), the total treatment duration was 14 days. Qualitative and quantitative analyses of GBPY were performed using Ultra-Performance Liquid Chromatography (UPLC). Metastasis was observed using hematoxylin and eosin (H&E) staining, and the expression of immune cells was assessed by flow cytometry and immunofluorescence staining. Mechanistic insights were gained through Western blot.

Results: The high-dose GBPY and gemcitabine groups showed significantly fewer lung metastatic tumors (P = .002; P < .001), while no significant difference was observed between the medium-dose group and control group (P = .438). Flow cytometry results indicated that high-dose GBPY significantly downregulated Myeloid-Derived Suppressor Cells (MDSCs) and G-MDSCs (P = .002 and P = .001, respectively), upregulated dendritic cells (DCs; P = .021), increased M1 macrophages (F4/80⁺/iNOS⁺; P = .001) and decreased M2 macrophages (CD206⁺ F4/80⁺) (P < .001). Furthermore, Western blot results showed that the high-dose GBPY group significantly inhibited the expression of p-JAK2, p-STAT3 (P = .013, P = .001 respectively).

Conclusions: The GBPY Formula may reduce lung cancer metastasis and recurrence by inhibiting the JAK2/STAT3 pathway, downregulating the presence of MDSCs, upregulating the proportion of DCs, and promoting the polarization of M2 macrophages to M1 macrophages. These changes enhance the anti-tumor immune response, contributing to the reduction of lung cancer metastasis and recurrence.