Tumor‐Associated Macrophages in the Chemoresistant Microenvironment of Gastric Cancer: Key Mechanisms and Intercellular Crosstalk

Gastric cancer (GC) remains a leading cause of cancer-related mortality, with chemoresistance posing a critical barrier to effective treatment. Tumor-associated macrophages (TAMs), particularly the immunosuppressive M2-polarized subset, are emerging as pivotal mediators of chemoresistance within the tumor microenvironment (TME). TAMs promote resistance through multifaceted mechanisms, including activation of pro-survival signaling pathways, induction of epithelial-mesenchymal transition (EMT), and enhancement of angiogenesis. For instance, M2-like TAMs secrete CXCL5, which activates the PI3K/AKT/mTOR axis in GC cells, thereby conferring resistance to 5-fluorouracil (5-FU). Similarly, TMEM, a transmembrane protein overexpressed in cisplatin-resistant GC, drives M2 polarization of TAMs via the Wnt/β-catenin pathway, further amplifying drug resistance and tumor progression. Clinical studies reveal that high TAM infiltration correlates with poor chemotherapy response and reduced survival in GC patients. This review synthesizes current evidence on TAM-driven chemoresistance in GC, highlighting the molecular interplay between TAMs, tumor cells, and stromal components. It underscores the potential of TAM-centric therapies-including checkpoint inhibitors, epigenetic modulators, and combination regimens-to overcome resistance and improve clinical outcomes. By integrating preclinical insights and clinical data, this work provides a roadmap for developing precision therapies that exploit TAM biology to enhance chemosensitivity in GC.

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