<p>Tumor-associated macrophages (TAMs) play a crucial role in fostering an immunosuppressive tumor microenvironment, promoting cancer progression, contributing to immune evasion and resistance to immunotherapy. However, the mechanisms by which TAMs exert these effects in gastric cancer (GC) remain unclear. Human TAMs were isolated from GC patients through magnetic sorting for RNA sequencing. THP-1 cell line and mice bone marrow-derived macrophages (BMDMs) induced TAMs were applied for functional assays. Two in-house tumor microarrays were utilized for validation: the Zhongshan Cohort, comprising 135 patients, and the Zhongshan Flow Cytometry (ZSFC) Cohort, which included 60 patients. In this study, we identified a significant accumulation of TREM2⁺ TAMs in GC tissues, correlating with poor prognosis. Functional assays revealed that targeting TREM2⁺ TAMs suppressed GC progression both in vitro and in vivo. Mechanistically, TREM2 stabilized signal transducer and activator of transcription 1 (STAT1) by preventing its ubiquitination mediated by Tripartite Motif Containing 21 (TRIM21), while simultaneously promoting STAT1 phosphorylation via spleen-associated tyrosine kinase (SYK), leading to upregulation of CCL8 and PD-L1, fostering an immunosuppressive tumor microenvironment. Furthermore, depletion of TREM2⁺ TAMs significantly enhanced the efficacy of anti-PD-L1 immunotherapy in GC allograft models. Collectively, our findings establish TREM2⁺ TAMs as key drivers of GC progression and immune evasion. Targeting TREM2⁺ TAMs represents a promising therapeutic strategy to overcome resistance to anti-PD-L1 therapy and reshape the tumor immune microenvironment.</p>