Research progress on tumor-associated macrophage polarization in gastric cancer immunotherapy resistance and its key signaling regulatory mechanisms_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHU Yuzhen ,  ZHANG Junqing

Department of Oncology, Shanxi Provincial People’s Hospital, Shanxi Medical University, Taiyuan 030012, P. R. China;

Corresponding?author：

ZHANG Junqing, Email: zhangjunqing0@126.com

Keywords：

gastric cancer; immunotherapy resistance; tumor-associated macrophage

DOI：

10.7507/1007-9424.202605072

Video：

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Objective To summarize the research progress on the role of tumor-associated macrophages (TAMs) polarization in gastric cancer immunotherapy resistance and its pivotal signaling-regulatory mechanisms. Method Recent domestic and international literature was systematically reviewed to summarize the distribution patterns of TAMs polarization phenotypes in the gastric cancer immune microenvironment, the mechanisms mediating immunotherapy resistance, the regulatory roles of key signaling pathways, and the TAMs-targeted intervention strategies. Results In gastric cancer, TAMs are characterized by an M2-like polarization-dominant continuous spectrum with marked spatial heterogeneity; they are enriched at the invasive front and remodeled via exosomes, lactylation, and other mechanisms. TAMs polarization is finely orchestrated by multiple signaling pathways, among which the CSF1R-STAT3/PPARγ (colony stimulating factor 1 receptor/signal transducer and activator of transcription 3/peroxisome proliferator-activated receptor gamma) axis is identified as the core driver of M2 polarization, while functional imbalance is observed in the TLR-NF-κB/IRF (Toll-like receptor/nuclear factor kappa B/interferon regulatory factor) pathway within the gastric cancer microenvironment due to epigenetic alterations. Immunotherapy resistance is driven by M2-like TAMs via the establishment of immunosuppressive networks, direct suppression of CD8⁺ T cell effector functions, metabolic reprogramming, and other mechanisms. Notably, glycolysis induced by the IL-4/IL-4R axis and the accumulation of IRG1 (immune-responsive gene 1) / itaconate play critical roles in this process. In preclinical gastric cancer models, therapeutic strategies such as CSF1R blockade, epigenetic reprogramming (such as DNA methyltransferase inhibitor, histone methyltransferase inhibitor), and nanodrug delivery systems have been shown to reverse TAMs polarization and restore immunotherapy sensitivity, although clinical evidence specific to gastric cancer remains scarce. Furthermore, molecular subtype heterogeneity (e.g., Epstein-Barr virus-positive, hepatoid adenocarcinoma of the stomach) and TAMs subset diversity (e.g., TREM2⁺, IL-10⁺, Siglec-10⁺) represent critical determinants of therapeutic responsiveness. Conclusions The polarization status of TAMs serves as a pivotal determinant of immunotherapy resistance in gastric cancer, while its regulatory mechanisms offer novel targets for combination therapies. Future strategies should integrate molecular subtypes with dynamic biomarkers to develop personalized TAMs-targeted interventions to overcome immunotherapy resistance.

Citation： ZHU Yuzhen, ZHANG Junqing. Research progress on tumor-associated macrophage polarization in gastric cancer immunotherapy resistance and its key signaling regulatory mechanisms. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2026, 33(8): 1143-1152. doi: 10.7507/1007-9424.202605072 Copy

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CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Research progress on tumor-associated macrophage polarization in gastric cancer immunotherapy resistance and its key signaling regulatory mechanisms

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