Traditional Chinese medicine modulates tumor-associated macrophages to suppress gastric cancer progression: mechanisms and therapeutic potential.

BACKGROUND: Gastric cancer (GC) remains a leading cause of cancer-related mortality, with progression driven largely by the tumor microenvironment (TME). Tumor-associated macrophages (TAMs), the most abundant immune cells in the GC stroma, drive immune evasion, angiogenesis, metastasis, and chemoresistance through polarization toward an M2-like phenotype. OBJECTIVE: This review aims to systematically consolidate the multifaceted molecular mechanisms by which TAMs promote GC aggressiveness and therapeutic resistance, and to categorize the current experimental evidence regarding Traditional Chinese Medicine (TCM) interventions that target TAM reprogramming for anti-GC therapy. METHODS: This narrative review summarizes current evidence retrieved from PubMed, Web of Science, Embase, Scopus, the Cochrane Library, CNKI, Wanfang Data, and the VIP Database from database inception to May 2026, with no language restrictions. The search strategy combined terms related to "gastric cancer" (e.g., gastric cancer, stomach cancer, gastric carcinoma), "tumor-associated macrophages" (e.g., tumor-associated macrophages, TAMs, macrophage polarization, M1 macrophages, M2 macrophages), and "Traditional Chinese Medicine" (e.g., traditional Chinese medicine, Chinese herbal medicine, herbal formula, natural product, active monomer, polysaccharide, terpenoid, alkaloid, catechin), using Boolean operators (AND, OR). Additional relevant studies were identified by manual screening of reference lists of included articles and relevant reviews. Studies were included if they investigated the biological roles of TAMs within the GC TME or the molecular mechanisms by which TCM modulates TAMs, covering both classical herbal formulae and bioactive monomers. RESULTS: Mechanistically, TAMs promote GC cell proliferation, invasion, and metastasis through the FOXQ1/EMT axis and exosomal ApoE/PI3K/AKT signaling pathways; promote angiogenesis through the VEGF/NF-κB and COX-2/MMP9 signaling pathways; induce resistance to 5-fluorouracil, cisplatin, and oxaliplatin via exosomal miR-21/PTEN, miR-1911-5p, and circ0008253; and mediate immune evasion through the PD-L1- and CLEVER-1-mediated immune checkpoint pathways. Therapeutically, TCM formulae, including Yi-qi-hua-yu-jie-du decoction and Jianpi Yangzheng formula, effectively reprogram TAMs by modulating the PP2A/PI3K/AKT/NF-κB signaling pathway and the exosomal miR-513b-5p/PTEN axis. Active monomers, including Actinidia eriantha polysaccharide, Dendrobium officinale polysaccharide, sophoridine, and epigallocatechin gallate, promote M1-like macrophage polarization and reverse M2-like macrophage-mediated immunosuppression through the PD-1/PD-L1, STAT6/PPAR-γ/JAGGED1/NOTCH1, and TLR4/IRF3 signaling pathways. CONCLUSIONS: TCM-mediated TAM reprogramming represents a promising adjunctive strategy to enhance chemotherapy and immunotherapy efficacy in GC.