TREM2‐Mediated Cholesterol Efflux in Macrophages Inhibits Anti‐Tumor Immunity via Limitation of CD4 ⁺ T and NK Cells

Tumor-associated macrophages (TAMs) predominantly exert functions that facilitate tumor progression. Triggering receptor expressed on myeloid cell 2 (TREM2) is expressed in TAMs, playing a crucial role in mediating the immunosuppressive function of TAMs. The mechanisms by which TREM2⁺ TAMs promote tumor growth and inhibit anti-tumor immunity remain unclear. Through single-cell sequencing of tumor tissues derived from wild-type and Trem2 knockout mice bearing subcutaneous lung cancer, it is found that TREM2 deletion hindered tumor growth, with a notable increase in and improved functionality of CD4⁺ T and natural killer (NK) cells in the tumor microenvironment. TREM2 deficiency led to ATP-binding cassette transporter A1 (ABCA1) downregulation, causing cholesterol accumulation in TAMs and promoting a pro-inflammatory phenotype. This results in increased chemokine (C-X3-C motif) ligand 1 (CX3CL1) secretion of macrophages, recruiting more CD4⁺ T and NK cells to the tumor site, enhancing the anti-tumor response. After screening food and drug administration (FDA)-approved drugs, bortezomib and ataluren are found to effectively inhibit TREM2 expression in TAMs, indicating a potential therapeutic strategy against TREM2. This study elucidates the mechanism by which TREM2 shapes the immunosuppressive microenvironment and promotes tumorigenesis, highlighting TREM2 as a target for cancer immunotherapy.