%0 Journal Article
%T Identification of hypoxic macrophages in glioblastoma with therapeutic potential for vasculature normalization.
%A Wang W
%A Li T
%A Cheng Y
%A Li F
%A Qi S
%A Mao M
%A Wu J
%A Liu Q
%A Zhang X
%A Li X
%A Zhang L
%A Qi H
%A Yang L
%A Yang K
%A He Z
%A Ding S
%A Qin Z
%A Yang Y
%A Yang X
%A Luo C
%A Guo Y
%A Wang C
%A Liu X
%A Zhou L
%A Liu Y
%A Kong W
%A Miao J
%A Ye S
%A Luo M
%A An L
%A Wang L
%A Che L
%A Niu Q
%A Ma Q
%A Zhang X
%A Zhang Z
%A Hu R
%A Feng H
%A Ping YF
%A Bian XW
%A Shi Y
%J Cancer Cell
%V 42
%N 5
%D 2024 May 13
%M 38640932
%F 38.585
%R 10.1016/j.ccell.2024.03.013
%X Monocyte-derived tumor-associated macrophages (Mo-TAMs) intensively infiltrate diffuse gliomas with remarkable heterogeneity. Using single-cell transcriptomics, we chart a spatially resolved transcriptional landscape of Mo-TAMs across 51 patients with isocitrate dehydrogenase (IDH)-wild-type glioblastomas or IDH-mutant gliomas. We characterize a Mo-TAM subset that is localized to the peri-necrotic niche and skewed by hypoxic niche cues to acquire a hypoxia response signature. Hypoxia-TAM destabilizes endothelial adherens junctions by activating adrenomedullin paracrine signaling, thereby stimulating a hyperpermeable neovasculature that hampers drug delivery in glioblastoma xenografts. Accordingly, genetic ablation or pharmacological blockade of adrenomedullin produced by Hypoxia-TAM restores vascular integrity, improves intratumoral concentration of the anti-tumor agent dabrafenib, and achieves combinatorial therapeutic benefits. Increased proportion of Hypoxia-TAM or adrenomedullin expression is predictive of tumor vessel hyperpermeability and a worse prognosis of glioblastoma. Our findings highlight Mo-TAM diversity and spatial niche-steered Mo-TAM reprogramming in diffuse gliomas and indicate potential therapeutics targeting Hypoxia-TAM to normalize tumor vasculature.