Institute of Pathology and Glioma Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), and the Key Laboratory of Tumour Immunopathology, The Ministry of Education of China, Chongqing, P. R. China.
Yu-Yue Pathology Scientific Research Center and Jinfeng Laboratory, Chongqing, P. R. China.
Clin Transl Med. 2024 Sep;14(9):e70013. doi: 10.1002/ctm2.70013.
Tumor-associatedmacrophages (TAMs) exhibit remarkable heterogeneity in glioblastoma. Spatially resolved single-cell transcriptomic studies identified a monocyte-derived TAM subset localized in the peri-necrotic niche, driven by hypoxic cues to acquire ahypoxia response signature. These hypoxia-TAMs destabilize endothelial adherens junctions through adrenomedullin paracrine signaling, promoting the formation of hyperpermeable neovasculature that impedes drug delivery. Blocking adrenomedullin produced by hypoxia-TAMs restores vascular integrity, increases drug deliveryinto tumors, and provides combinatorial therapeutic benefits. Here we discuss the heterogeneity of TAMs regarding functional states and locations in glioblastomas, and propose future directions for studying the temporospatial dynamics of multifaceted TAM. HIGHLIGHTS: Single-cell omics reveal a functionally and spatially distinct hypoxia-TAM subset in glioblastoma. Adrenomedullin secreted by hypoxia-TAM destabilizes tumor vasculature and its blockade enhances vessel integrity and drug delivery.
肿瘤相关巨噬细胞（TAMs）在胶质母细胞瘤中表现出显著的异质性。空间分辨的单细胞转录组学研究鉴定出一种位于坏死周围龛位的单核细胞衍生的 TAM 亚群，受缺氧信号驱动获得缺氧反应特征。这些缺氧-TAMs 通过肾上腺髓质素旁分泌信号破坏内皮细胞黏附连接，促进形成通透性增加的新生血管，阻碍药物输送。阻断缺氧-TAMs 产生的肾上腺髓质素可恢复血管完整性，增加药物输送到肿瘤中，并提供联合治疗益处。在这里，我们讨论了 TAMs 关于功能状态和在胶质母细胞瘤中的位置的异质性，并提出了研究多方面 TAM 的时空动态的未来方向。重点：单细胞组学揭示了胶质母细胞瘤中具有功能和空间差异的缺氧-TAM 亚群。缺氧-TAM 分泌的肾上腺髓质素破坏肿瘤血管，其阻断可增强血管完整性和药物输送。
