Tumor-associated macrophages: emerging insights of immunotherapy in gastric cancer

Abstract Gastric cancer exhibits a high mortality rate, and a significant reason for its limited response to systemic therapy is the substantial enrichment of tumor-associated macrophages and their potent immunosuppressive functions. The high plasticity of TAMs in both phenotype and metabolism enables them to adopt multiple pro-tumorigenic states, driving tumor progression, immune evasion, angiogenesis, and therapy resistance. This review summarizes the origin, polarization, metabolic remodeling, and cellular interactions of TAMs within the tumor microenvironment of gastric cancer. It also highlights key mechanisms—such as PI3Kγ-driven aberrant lipid metabolism, exosome-mediated reprogramming, and stroma–macrophage signaling—that collectively enhance the formation of pro-tumorigenic TAM subsets and contribute to resistance against chemotherapy, HER2-targeted therapy, and immune checkpoint inhibition. Furthermore, we discuss emerging TAM-targeting strategies, including blockade of the CCL2/CCR2 and CSF-1/CSF-1R axes, macrophage reprogramming, chimeric antigen receptor macrophages (CAR-M) therapy, and nanotechnology-based macrophage modulation. We further highlight how dual-targeting CAR-M designs and macrophage-centered nanodelivery platforms may help convert TAM-rich “cold” tumors into immunologically active “hot” tumors.