M2-polarized tumor-associated macrophages as key orchestrators of gastric cancer pathogenesis and therapeutic resistance.

This article systematically reviews the central role of M2 tumor-associated macrophages (M2-TAMs) in the tumor microenvironment of gastric cancer. M2-TAMs originate from circulating monocytes, which are recruited by tumor chemokines and polarized into a pro-tumor phenotype under the influence of factors such as IL-4 and IL-10. They can be further divided into functionally cooperative subtypes M2a, M2b, M2c, and M2d, each playing distinct roles in the initiation and progression of gastric cancer: activating key signaling pathways such as PI3K/Akt/mTOR and JAK/STAT3 through cytokine secretion, and utilizing exosomes to deliver functional non-coding RNAs that directly promote tumor cell proliferation, invasion, and survival; driving angiogenesis and lymphangiogenesis by secreting factors such as VEGF, thus paving the way for the growth and metastasis of gastric malignant tumors; constructing a robust immunosuppressive microenvironment by highly expressing PD-L1, secreting inhibitory cytokines, and recruiting regulatory T cells, thereby mediating immune escape; promoting glycolysis and lactate metabolism, forming a self-reinforcing metabolic-immunosuppressive axis with tumor cells; In addition, they promote metastasis and contribute to chemotherapy and immunotherapy resistance through complex interactions with cancer cells and fibroblasts at specific metastatic sites such as the peritoneum and liver. Based on their pivotal position, strategies targeting M2-TAMs, such as blocking their recruitment, repolarizing them to an anti-tumor phenotype, or inhibiting their function, have become a highly promising new direction for therapy. Future research needs to further elucidate their heterogeneity and, through rational clinical trial design, promote the combination of these strategies with existing therapies, aiming to fundamentally improve the treatment landscape of gastric cancer.