Identification of hypoxic macrophages in glioblastoma with therapeutic potential for vasculature normalization

Cancer Cell. 2024 May 13;42(5):815-832.e12. doi: 10.1016/j.ccell.2024.03.013. Epub 2024 Apr 18.


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.

Keywords: adrenomedullin; dabrafenib; glioblastoma; glioma; hypoxia; necrosis; single-cell transcriptomics; spatial transcriptomics; tumor-associated macrophages; vasculature normalization.

MeSH terms

  • Adrenomedullin* / genetics
  • Adrenomedullin* / metabolism
  • Animals
  • Brain Neoplasms* / blood supply
  • Brain Neoplasms* / drug therapy
  • Brain Neoplasms* / genetics
  • Brain Neoplasms* / metabolism
  • Brain Neoplasms* / pathology
  • Cell Hypoxia
  • Cell Line, Tumor
  • Glioblastoma* / blood supply
  • Glioblastoma* / drug therapy
  • Glioblastoma* / genetics
  • Glioblastoma* / metabolism
  • Glioblastoma* / pathology
  • Humans
  • Isocitrate Dehydrogenase / genetics
  • Macrophages / metabolism
  • Mice
  • Neovascularization, Pathologic / genetics
  • Tumor Microenvironment
  • Tumor-Associated Macrophages* / metabolism
  • Xenograft Model Antitumor Assays