Single-cell profiling of myeloid cells in glioblastoma across species and disease stage reveals macrophage competition and specialization
Open accessAbstract
Glioblastomas are aggressive primary brain cancers that recur as therapy-resistant tumors. Myeloid cells control glioblastoma malignancy, but their dynamics during disease progression remain poorly understood. Here, we employed single-cell RNA sequencing and CITE-seq to map the glioblastoma immune landscape in mouse tumors and in patients with newly diagnosed disease or recurrence. This revealed a large and diverse myeloid compartment, with dendritic cell and macrophage populations that were conserved across species and dynamic across disease stages. Tumor-associated macrophages (TAMs) consisted of microglia- or monocyte-derived populations, with both exhibiting additional heterogeneity, including subsets with conserved lipid and hypoxic signatures. Microglia- and monocyte-derived TAMs were self-renewing populations that competed for space and could be depleted via CSF1R blockade. Microglia-derived TAMs were predominant in newly diagnosed tumors, but were outnumbered by monocyte-derived TAMs following recurrence, especially in hypoxic tumor environments. Our results unravel the glioblastoma myeloid landscape and provide a framework for future therapeutic interventions.
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The inhibitor-based protocol offers greater experimental and tissue-/cell-type flexibility than previously developed experimental and computational solutions.
“Our inhibitor-based protocol offers much greater experimental and tissue-/cell-type flexibility than previously developed experimental and computational solutions for this pervasive issue (see additional discussion of some alternative methods in Supplementary Note 7)33,34,45,65,67,68.”
From Dissection of artifactual and confounding glial signatures by single-cell sequencing of mouse and human brain (2022) · cites this paper as [68]
Single-cell transcriptomics has revealed the presence of numerous subsets/states of macrophages in any given injured tissue in humans.
“The growing accessibility of single-cell transcriptomics has also revealed the presence of numerous subsets/states of macrophages in any given injured tissue in humans (30–33).”
From Targeting macrophages in liver fibrosis (2026) · cites this paper as [33]
The LAM phenotype is not unique to the fibrotic liver, also being identified in other tissues in the context of sterile injury as well as in macrophages surrounding the bile duct in the healthy liver.
“Interestingly, this phenotype is not unique to the fibrotic liver, also being identified in other tissues in the context of sterile injury (32, 33, 38, 110–121) as well as in macrophages surrounding the bile duct in the healthy liver (62).”
From Targeting macrophages in liver fibrosis (2026) · cites this paper as [33]
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TREM2 inhibition triggers antitumor cell activity of myeloid cells in glioblastoma
Sun, R., Han, R., McCornack, C., Khan, S., Tabor, G. T., Chen, Y., Hou, J., Jiang, H., Schoch, K. M., Mao, D. D., et al. (2023) · Science Advances · doi:10.1126/sciadv.ade3559 · Cited by 119 · see citing works
Characterizing cellular heterogeneity in chromatin state with scCUT&Tag-pro
Zhang, B., Srivastava, A., Mimitou, E., Stuart, T., Raimondi, I., Hao, Y., Smibert, P., & Satija, R. (2022) · Nature Biotechnology · doi:10.1038/s41587-022-01250-0 · Cited by 104 · see citing works
Spatially restricted and ontogenically distinct hepatic macrophages are required for tissue repair
De Ponti, F. F., Bujko, A., Liu, Z., Collins, P. J., Schuermans, S., Maueroder, C., Amstelveen, S., Thoné, T., Martens, L., McKendrick, J. G., et al. (2025) · Immunity · doi:10.1016/j.immuni.2025.01.002 · Cited by 94 · see citing works
Self-citationMechanism and therapeutic potential of tumor-immune symbiosis in glioblastoma
Pang, L., Khan, F., Heimberger, A. B., & Chen, P. (2022) · Trends in Cancer · doi:10.1016/j.trecan.2022.04.010 · Cited by 67 · see citing works
Barca, C., Foray, C., Hermann, S., Herrlinger, U., Remory, I., Laoui, D., Schäfers, M., Grauer, O. M., Zinnhardt, B., & Jacobs, A. H. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.787307 · Cited by 64 · see citing works
Pharmacological targeting of the tumor–immune symbiosis in glioblastoma
Pang, L., Khan, F., Dunterman, M., & Chen, P. (2022) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2022.04.002 · Cited by 36 · see citing works
Tumor-associated macrophages: Prognostic and therapeutic targets for cancer in humans and dogs
Brady, R. V., & Thamm, D. H. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1176807 · Cited by 35 · see citing works
Targeting macrophages in liver fibrosis
González del Barrio, L., Ipsen, D. H., Pfister, D. R., Hancz, D., & Scott, C. L. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1835489 · Cited by 3 · see citing works
- Authors
- Pombo Antunes, A. R., Scheyltjens, I., Lodi, F., Messiaen, J., Antoranz, A., Duerinck, J., Kancheva, D., Martens, L., De Vlaminck, K., Van Hove, H., Kjølner Hansen, S. S., Bosisio, F. M., Van der Borght, K., De Vleeschouwer, S., Sciot, R., Bouwens, L., Verfaillie, M., Vandamme, N., Vandenbroucke, R. E., De Wever, O., Saeys, Y., Guilliams, M., Gysemans, C., Neyns, B., De Smet, F., Lambrechts, D., Van Ginderachter, J. A., & Movahedi, K.
- Affiliations
- Vrije Universiteit Brussel (BE)
- VIB-KU Leuven Center for Cancer Biology (BE)
- KU Leuven (BE)
- Universitair Ziekenhuis Brussel (BE)
- Janssen (Belgium) (BE)
- Ghent University (BE)
- Europe Hospitals (BE)
- Corresponding author
- Movahedi, Kiavash
- ORCID
- Scheyltjens, Isabelle
- Lodi, Francesca
- Messiaen, Julie
- Antoranz, Asier
- Duerinck, Johnny
- Kancheva, Daliya
- Martens, Liesbet
- De Vlaminck, Karen
- Van Hove, Hannah
- Bosisio, Francesca Maria
- De Vleeschouwer, Steven
- Sciot, Raf
- Bouwens, Luc
- Vandamme, Niels
- Vandenbroucke, Roosmarijn E.
- Saeys, Yvan
- Guilliams, Martin
- Gysemans, Conny
- Neyns, Bart
- De Smet, Frederik
- Lambrechts, Diether
- Movahedi, Kiavash
- Venue
- Nature Neuroscience
- Published
- 2021-03-29
- Volume
- 24
- Issue
- 4
- Pages
- 595-610
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W3150063851
- Semantic Scholar
- 53bce8823e5821db95553d059dd6a254aac1f3b8
- Cited by
- 704
- References
- 75
- Citations by year
- 2026: 134 · 2025: 139 · 2024: 155 · 2023: 135 · 2022: 97 · 2021: 43
- FWCI
- 42.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Lirias (KU Leuven) (submittedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Funders
- Fonds Wetenschappelijk Onderzoek (G0I1118N)
- EC | Horizon 2020 Framework Programme (766069)
- KU Leuven (C14/17/084)
- Agentschap Innoveren en Ondernemen (HBC.2016.0889)
- Innoviris (BB2B 2015-2)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- glioblastoma, myeloid cells, tumor-associated macrophages, microglia, monocyte-derived macrophages, tumor immune microenvironment, tumor recurrence, hypoxia, lipid metabolism, CSF1R blockade, dendritic cells, cross-species comparison, mouse model
- MeSH terms
- Tumor-Associated Macrophages, Animals, Brain Neoplasms, Glioblastoma, Humans, Mice, Single-Cell Analysis
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