Therapeutic potential of targeting macrophage polarization in metastatic gastric cancer: a review on core mechanisms and clinical progress

Gastric cancer remains a leading cause of cancer-related mortality worldwide, with high metastatic potential being a critical factor for poor prognosis. Notably, the objective response rate (ORR) of current immunotherapies, such as immune checkpoint inhibitors (ICIs), remains below 20%. Within the tumor microenvironment (TME), the dynamic interactions among immune cells profoundly regulate tumor progression, in which the remarkable plasticity of tumor-associated macrophages (TAMs) plays a pivotal role. Under the induction of microenvironmental signals, TAMs can polarize into either the anti-tumor M1 phenotype or the pro-tumor M2 phenotype. This review summarizes the research progress of macrophage polarization in distant metastasis of gastric cancer, with a specific focus on the regulatory mechanisms of core signaling pathways, including STAT3, PI3K/AKT, and exosomal ncRNA regulatory networks, in macrophage functional reprogramming and metastatic niche formation. Furthermore, we discuss potential immunotherapy strategies centered on modulating macrophage phenotypes, such as CSF1R inhibitors, CD47 blockers, and their combination with ICIs. These findings provide a significant foundation for developing macrophage-targeted therapeutic interventions, screening translational biomarkers, and improving the prognosis of patients with metastatic gastric cancer.