胶质母细胞瘤（GBM）是一种无法治愈的中枢神经系统（CNS）癌症，其特征是大量骨髓细胞浸润。在外周非 CNS 癌症中确定的骨髓细胞定向治疗靶点是否适用于 GBM 需要进一步研究。在这里，我们确定了周围癌症中关键的免疫抑制靶点，即触发髓样细胞 2 (TREM2) 上表达的受体，在 GBM 中具有免疫保护作用。遗传或药理学 TREM2 缺陷会促进体内 GBM 进展。单细胞和空间测序揭示 GBM 浸润的骨髓细胞中 TREM2 下调。 TREM2 与 GBM 中的免疫抑制性骨髓和 T 细胞耗竭特征呈负相关。我们进一步证明，在 GBM 进展过程中，富含 CNS 的鞘脂结合骨髓细胞上的 TREM2 并引发抗肿瘤反应。临床上，骨髓细胞中 TREM2 的高表达与 GBM 更好的生存相关。腺相关病毒介导的 TREM2 过度表达可阻碍 GBM 进展并与抗 PD-1 疗法产生协同作用。我们的结果揭示了 TREM2 在 CNS 癌症中的独特功能，并支持癌症免疫治疗中的器官特异性骨髓细胞重塑。版权所有 © 2024 Elsevier Inc. 保留所有权利。

Glioblastomas (GBM) are incurable central nervous system (CNS) cancers characterized by substantial myeloid cell infiltration. Whether myeloid cell-directed therapeutic targets identified in peripheral non-CNS cancers are applicable to GBM requires further study. Here, we identify that the critical immunosuppressive target in peripheral cancers, triggering receptor expressed on myeloid cells-2 (TREM2), is immunoprotective in GBM. Genetic or pharmacological TREM2 deficiency promotes GBM progression in vivo. Single-cell and spatial sequencing reveals downregulated TREM2 in GBM-infiltrated myeloid cells. TREM2 negatively correlates with immunosuppressive myeloid and T cell exhaustion signatures in GBM. We further demonstrate that during GBM progression, CNS-enriched sphingolipids bind TREM2 on myeloid cells and elicit antitumor responses. Clinically, high TREM2 expression in myeloid cells correlates with better survival in GBM. Adeno-associated virus-mediated TREM2 overexpression impedes GBM progression and synergizes with anti-PD-1 therapy. Our results reveal distinct functions of TREM2 in CNS cancers and support organ-specific myeloid cell remodeling in cancer immunotherapy.Copyright © 2024 Elsevier Inc. All rights reserved.