What question did this study set out to answer?

The study aims to investigate the mechanisms through which Yi-qi-hua-yu-jie-du decoction (YJD) inhibits gastric cancer by modulating tumor-associated macrophage polarization.

May 14, 2026Open Access

Yi-qi-hua-yu-jie-du Decoction Inhibits Gastric Cancer Progression by Inducing Tumor-Associated Macrophage Polarization via Modulating PP2A Enzyme Activity to Mediate the PI3K/AKT/NF-κB Axis

PYPeipei YangNanjing University of Chinese Medicine WHWenjie HuangNanjing University of Chinese Medicine QLQiurong LiNanjing University of Chinese Medicine

Key Points

The study aims to investigate the mechanisms through which Yi-qi-hua-yu-jie-du decoction (YJD) inhibits gastric cancer by modulating tumor-associated macrophage polarization.
Network pharmacology identified targets/pathways for YJD's action on TAMs in gastric cancer.
A tumor cell-macrophage co-culture system was developed for assessing YJD’s effects on phenotype conversion and cell behaviors.
In vivo assessments using BALB/c nude mice xenograft models were conducted to evaluate antitumor activity and safety.
YJD significantly inhibited tumor growth and reduced M2-type tumor-associated macrophages in vivo. Effect sizes were not quantified but indicated substantial efficacy.
In vitro data showed YJD promoted M1 polarization, inhibited gastric cell proliferation, induced apoptosis, and reversed epithelial-mesenchymal transition.
Mechanistically, YJD enhanced PP2A activity, suppressed the PI3K/AKT axis, and modulated NF-κB signaling, with effects blocked by a PP2A inhibitor.

Abstract

Background: Gastric cancer (GC) is a major global malignancy with high recurrence and metastasis rates. Yi-qi-hua-yu-jie-du decoction (YJD) demonstrates clinical efficacy in reducing these risks. However, its mechanism of modulating tumor-associated macrophages (TAMs) in GC remains unclear. This study aimed to investigate YJD’s inhibitory effects via TAM polarization and uncover the underlying mechanisms. Methods: Network pharmacology identified key targets/pathways for YJD’s action on TAMs in GC, with binding affinities assessed. A tumor cell-macrophage co-culture system was developed to investigate YJD’s impacts on TAM phenotype conversion, malignant cell proliferation, apoptotic induction, and epithelial-mesenchymal transition (EMT) progression. BALB/c nude mice GC xenografts models were established to assess YJD’s in vivo antitumor activity, safety profile, and TME modulation. Techniques including cell viability assays, Western blotting, flow cytometry, wound healing assays, PP2A activity assays, immunofluorescence, and immunohistochemistry were employed to validate the proposed mechanism. Results: YJD active components exhibit high-affinity binding sites with the PP2A catalytic subunit. Key enriched pathways for YJD-regulated macrophage polarization included PI3K-AKT and NF-κB. YJD significantly inhibited tumor growth, reduced M2-type TAMs in vivo, and exhibited a favorable safety profile. In vitro, YJD promoted M1 polarization, inhibited gastric cells proliferation, induced apoptosis, and reversed EMT. Mechanistically, YJD enhanced PP2A activity, suppressed the PI3K/AKT axis, and modulated NF-κB signaling to drive M1 polarization—effects blocked by a PP2A inhibitor. Conclusion: YJD suppresses GC progression through PP2A-dependent modulation of the PI3K/AKT/NF-κB axis, shifting TAM polarization toward the anti-tumor M1 phenotype. This elucidates the pharmacological basis of YJD’s anti-tumor effects and supports its clinical potential. Keywords: Yi-qi-hua-yu-jie-du decoction, PP2A, tumor-associated macrophage, gastric cancer

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