{Reference Type}: Journal Article
{Title}: Identification of hypoxic macrophages in glioblastoma with therapeutic potential for vasculature normalization.
{Author}: Wang W;Li T;Cheng Y;Li F;Qi S;Mao M;Wu J;Liu Q;Zhang X;Li X;Zhang L;Qi H;Yang L;Yang K;He Z;Ding S;Qin Z;Yang Y;Yang X;Luo C;Guo Y;Wang C;Liu X;Zhou L;Liu Y;Kong W;Miao J;Ye S;Luo M;An L;Wang L;Che L;Niu Q;Ma Q;Zhang X;Zhang Z;Hu R;Feng H;Ping YF;Bian XW;Shi Y;
{Journal}: Cancer Cell
{Volume}: 42
{Issue}: 5
{Year}: 2024 May 13
{Factor}: 38.585
{DOI}: 10.1016/j.ccell.2024.03.013
{Abstract}: 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.