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

作者：Yunhan Wang, Weina Yu, Xinxin Wang, Qitai Zhao, Qingyang Lei, Aitian Li, Shasha Liu, Tian Wang, Li Yang, Yi Zhang · 发表于：Advanced Science · 年份：2025 · DOI：10.1002/advs.202506995 · 被引用次数：3 · 研究领域：Immune cells in cancer、Immune Cell Function and Interaction、Neuroinflammation and Neurodegeneration Mechanisms

Abstract 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.