Immune modulation in gastric cancer: from macrophage polarization to immunotherapy

Abstract

Gastric cancer remains a highly lethal malignancy characterized by late diagnosis, limited therapeutic responsiveness, and a profoundly immunosuppressive tumor microenvironment. Among the diverse cellular components shaping this ecosystem, tumor-associated macrophages (TAMs) have emerged as central orchestrators of gastric carcinogenesis, metastatic dissemination, and therapeutic resistance. TAMs promote tumor initiation through inflammatory recruitment and polarization, facilitate invasion and angiogenesis via cytokines, matrix-remodeling enzymes, and exosomal cargo, and impair antitumor immunity by suppressing T-cell and natural killer cell function. In addition, TAMs contribute to resistance to immune checkpoint blockade by sustaining an immunosuppressive tumor immune microenvironment enriched in Tregs, myeloid-derived suppressor cells, and inhibitory mediators such as TGF-β, IL-10, and PD-L1. Recent advances further highlight the translational promise of macrophage-targeted strategies, including polarization reprogramming, recruitment blockade, and chimeric antigen receptor macrophage therapy. Previous reviews primarily focus on the general biological roles of TAMs, this review synthesizes newly emerging mechanisms of TAM-mediated immunotherapy resistance, including spatial heterogeneity, stromal-vascular remodeling, and exosomal crosstalk, with the latest clinical advances in macrophage-directed immunotherapies. We specifically highlight the translational potential and current clinical trial landscape of chimeric antigen receptor macrophage (CAR-M) therapy and targeted reprogramming strategies, providing a forward-looking perspective on overcoming immune checkpoint blockade resistance in gastric cancer.