Targeting TREM2+tumor-associated macrophages reactivates antitumor immunity and improves anti-PD-1 efficacy in gastric cancer.

BACKGROUND We have demonstrated that CXCL8⁺ monocyte-derived tumor-associated macrophages (TAMs) promote autonomous PD-L1 expression, thereby fostering an immunosuppressive tumor microenvironment. Nevertheless, the functional contribution of tissue-resident macrophages to immune escape remains largely unexplored. METHODS The study incorporated four independent cohorts, including two tumor microarray datasets and two groups of transcriptomic profiling data. Associations between TREM2⁺TAMs and clinical outcomes as well as genomic features were evaluated. Additionally, ex vivo culture of fresh tumor tissues was conducted to evaluate the potential therapeutic efficacy of dual blockade targeting PD-1 and TREM2 in gastric cancer. RESULTS TREM2⁺TAMs level was significantly associated with reduced overall survival in patients with resectable gastric cancer. Notably, a high density of TREM2⁺TAMs correlated with poorer response to immune checkpoint inhibitor. Mechanistically, TREM2⁺TAMs were found to drive CD8⁺T cell exhaustion through dual expression of PD-L1 and Arg1. Blockade of TREM2 sensitized tumors to pembrolizumab and enhanced antitumor immunity, particularly in tumors with high TREM2⁺TAMs infiltration. CONCLUSIONS TREM2⁺TAMs infiltration served as an independent prognosticator in patients with gastric cancer. TREM2⁺TAMs promoted tumor immune escape through concomitant expression of PD-L1 and Arg1. Dual blockade targeting both PD-1 and TREM2 enhanced antitumor responses in TREM2⁺TAMshigh tumors, suggesting a promising therapeutic strategy for gastric cancer.