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

Peipei Yang,1,2,* Wenjie Huang,3,* Qiurong Li,1,2 Zeyu Tu,1,2 Wenqin Ren,1,2 Xinyan Shu,1,2 Tianlu Chu,1,2 Peng Shu1,2 1Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, 210029, People’s Republic of China; 2The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, 210023, People’s Republic of China; 3School of Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, 210023, People’s Republic of China*These authors contributed equally to this workCorrespondence: Peng Shu, Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, No. 155, Hanzhong Road, Qinhuai District, Nanjing, Jiangsu Province, 210029, People’s Republic of China, Tel +025 86617141, Email [email protected]: 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