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

Abstract

	•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.

Keywords

glioblastoma / tumor-associatedmacrophage (TAM) / tumor vascular normalization

References

[1] HorbinskiC, BergerT, PackerRJ, Wen PY. Clinical implications of the 2021 edition of the WHO classification of central nervous system tumours. Nat Rev Neurol. 2022; 18(9): 515-529.

[2] HambardzumyanD, Gutmann DH, KettenmannH. The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci. 2016; 19(1): 20-27.

[3] WangW, LiT, ChengY, et al. Identification of hypoxic macrophages in glioblastoma with therapeutic potential for vasculature normalization. Cancer Cell. 2024; 42(5): 815-832. e12.

[4] GreenwaldAC, Darnell NG, HoefflinR, et al. Integrative spatial analysis reveals a multi-layered organization of glioblastoma. Cell. 2024; 187(10): 2485-2501. e26.

[5] KirschenbaumD, XieK, IngelfingerF, et al. Time-resolved single-cell transcriptomics defines immune trajectories in glioblastoma. Cell. 2024; 187(1): 149-165. e23.

[6] SattirajuA, KangS, GiottiB, et al. Hypoxic niches attract and sequester tumor-associated macrophages and cytotoxic T cells and reprogram them for immunosuppression. Immunity. 2023; 56(8): 1825-1843 e6.

[7] MantovaniA, Allavena P, MarchesiF, GarlandaC. Macrophages as tools and targets in cancer therapy. Nat Rev Drug Discov. 2022; 21(11): 799-820.

[8] ChenZ, FengX, HertingCJ, et al. Cellular and molecular identity of tumor-associated macrophages in glioblastoma. Cancer Res. 2017; 77(9): 2266-2278.

[9] ShiY, PingYF, ZhouW, et al. Tumour-associated macrophages secrete pleiotrophin to promote PTPRZ1 signalling in glioblastoma stem cells for tumour growth. Nat Commun. 2017; 8: 15080.

[10] RashidiA, Billingham LK, ZolpA, et al. Myeloid cell-derived creatine in the hypoxic niche promotes glioblastoma growth. Cell Metab. 2024; 36(1): 62-77. e8.

[11] WuL, WuW, ZhangJ, et al. Natural coevolution of tumor and immunoenvironment in glioblastoma. Cancer Discov. 2022; 12(12): 2820-2837.

[12] ZhongJ, XingX, GaoY, et al. Distinct roles of TREM2 in central nervous system cancers and peripheral cancers. Cancer Cell. 2024; 42(6): 968-984. e9.

[13] MolgoraM, Esaulova E, VermiW, et al. TREM2 modulation remodels the tumor myeloid landscape enhancing anti-PD-1 immunotherapy. Cell. 2020; 182(4): 886-900. e17.

[14] TanJ, FanW, LiuT, et al. TREM2(+) macrophages suppress CD8(+) T-cell infiltration after transarterial chemoembolisation in hepatocellular carcinoma. J Hepatol. 2023; 79(1): 126-140.

[15] ZhangL, LiZ, SkrzypczynskaKM, et al. Single-cell analyses inform mechanisms of myeloid-targeted therapies in colon cancer. Cell. 2020; 181(2): 442-459. e29.

[16] ChengS, LiZ, GaoR, et al. A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells. Cell. 2021; 184(3): 792-809. e23.

[17] ChenC, LiaoY, PengG. Connecting past and present: single-cell lineage tracing. Protein Cell. 2022; 13(11): 790-807.

[18] BleriotC, Dunsmore G, Alonso-CurbeloD, GinhouxF. A temporal perspective for tumor-associated macrophage identities and functions. Cancer Cell. 2024; 42(5): 747-758.

[19] GretenFR, Grivennikov SI. Inflammation and cancer: triggers, mechanisms, and consequences. Immunity. 2019; 51(1): 27-41.

RIGHTS & PERMISSIONS

2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.