Identification of hypoxic macrophages in glioblastoma: Unveiling therapeutic insights from tumour microenvironment analysis

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Clinical and Translational Medicine Pub Date : 2024-09-19 DOI:10.1002/ctm2.70013

Zhen Qin, Xiu-Wu Bian, Yu Shi

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Abstract

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.

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识别胶质母细胞瘤中的缺氧巨噬细胞：从肿瘤微环境分析中揭示治疗思路

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。空间分辨单细胞转录组研究发现，单核细胞衍生的 TAM 亚群定位在坏死周围的龛位中，在缺氧线索的驱动下获得缺氧反应特征。这些缺氧-TAM 通过肾上腺髓质素旁分泌信号破坏内皮粘连接头的稳定性，促进形成阻碍药物输送的高渗透性新血管。阻断缺氧-TAMs 产生的肾上腺髓质素可以恢复血管完整性，增加向肿瘤内的药物输送，并提供综合治疗效果。在此，我们讨论了胶质母细胞瘤中 TAMs 在功能状态和位置方面的异质性，并提出了研究多元 TAM 时空动态的未来方向。亮点单细胞组学揭示了胶质母细胞瘤中功能和空间上不同的缺氧-TAM亚群。低氧-TAM分泌的肾上腺髓质素能破坏肿瘤血管的稳定性，阻断肾上腺髓质素能增强血管的完整性和药物输送。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.