Elevated Triggering Receptor Expressed on Myeloid Cells 2 Expression in Tumor-Associated Macrophages Suppresses Cytotoxic T Cell Infiltration and Facilitates Immune Escape in Colorectal Cancer

Emerging evidence supports a crucial role for tumor-associated macrophages (TAMs) in shaping the immunosuppressive tumor microenvironment. Furthermore, research has identified the triggering receptor expressed on myeloid cells 2 (TREM2) has immunomodulatory functions. The present investigated the potential effect of TREM2 expression in TAMs on facilitating immune evasion in colorectal cancer (CRC). Immunohistochemical analysis of clinical specimens, complemented by extensive data mining from The Cancer Genome Atlas, revealed a significant upregulation of TREM2 in CRC-associated TAMs, with this upregulation exhibiting a correlation with poor patient prognosis. Mechanistically, TREM2 + TAMs were found to drive fibroblast activation through transforming growth factor-β (TGF-β) signaling, inducing fibroblast-activated protein (FAP)-positive cancer-associated fibroblasts (CAFs) that secrete collagen I/III to establish dense peritumoral barriers. Spatial profiling revealed that these fibrous structures physically impede CD8 + T-cell infiltration, restricting cytotoxic lymphocytes to stromal compartments. Intriguingly, TREM2 deficiency enhanced the secretion of matrix metalloproteinase 13 by macrophages, thereby promoting extracellular matrix degradation and improving T-cell penetration. In vivo, Trem2 -knockout mice showed a reduction in tumor growth with enhanced intratumoral CD8 + T-cell infiltration compared with wild-type controls. Our findings establish TREM2 + TAMs as central regulators of stromal remodeling and suggest that therapeutic targeting of the TREM2/TGF-β/FAP pathway may overcome immune resistance in CRC patients.