Single-cell profiling identifies a pro-tumoral VCAN positive macrophage subset and defines a prognostic signature in glioblastoma.

Overview

1. Department of Neurology, The First Affiliated Hospital of Yangtze University, Jingzhou First People’s Hospital,Jingzhou, 434000 China
2. Graduate student, Yangtze University,Jingzhou, 434000 China
3. Department of Neurosurgery, The First Affiliated Hospital of Yangtze University, Jingzhou First People’s Hospital,Jingzhou, 434000 China
4. Postgraduate training base Alliance of Wenzhou Medical University,Wenzhou, 325035 Zhejiang China
5. Department of Neurosurgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences,Hangzhou, 310022 Zhejiang China
6. Department of Oncology, The First Affiliated Hospital of Yangtze University, Jingzhou First People’s Hospital,Jingzhou, 434000 China

Abstract

Glioblastoma (GBM), the most aggressive primary brain tumor, develops within a tumor microenvironment (TME) dominated by tumor-associated macrophages (TAMs) that critically influence disease progression. Through single-cell RNA sequencing (scRNA-seq) and bioinformatic analysis, we delineated macrophage heterogeneity within the GBM TME and identified a distinct VCAN⁺ macrophage subpopulation. Pseudotime trajectory analysis revealed these cells at the terminal stage of macrophage differentiation, where they exhibit enhanced granulocyte migration and chemotaxis pathways and exhibit a pro-tumorigenic phenotype that diverges from classical M1/M2 polarization. These VCAN⁺ macrophages displayed a distinct polarization state driven by tumor necrosis factor-α (TNF-α), contributing to both a pro-inflammatory and an immunosuppressive TME. CellChat analysis demonstrated their pivotal role in intercellular communication—predominantly mediating crosstalk with GBM tumor cells, endothelial cells, and CD8⁺ T cells via SPP1 signaling: SPP1 binding to CD44 on tumor cells enhances their invasiveness, while its interaction with CD47 on CD8⁺ T cells inhibits anti-tumor immunity. Transcriptional regulatory network analysis identified that CDX2 and MXI1 serve as key transcription factors modulating VCAN⁺ macrophage function and maintaining their specific polarization and homeostasis. Through machine learning, we identified seven hub genes—C1QA, C1QC, C3, CCL4, CD44, SERPINE1, and TREM2 (all highly expressed in VCAN⁺ macrophages and involved in their polarization or intercellular communication)—and constructed an effective GBM prognostic model (AUC = 0.83 in validation cohort), underscoring their roles in immune regulation, extracellular matrix remodeling, and VCAN⁺ macrophage-mediated tumor progression. Further studies with larger cohorts and functional validation will clarify this subpopulation’s therapeutic potential and spatial distribution patterns.

Supplementary Information: The online version contains supplementary material available at 10.1007/s12672-026-05166-y.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Data links

• ncbi.nlm.nih.gov/geo, NCBI; found in the text, “Data acquisition and preprocessing”

Data availability

The datasets used and/or analyzed during the current study are publicly available from the following official repositories:1.GSE162631: https://www.ncbi.nlm.nih.gov/gds/?term=GSE1626312.Chinese Glioma Genome Atlas (CGGA): http://www.cgga.org.cn/index.jsp. The glioma mRNA sequencing datasets PRJCA001747 (n=693, https://ngdc.cncb.ac.cn/bioproject/browse/PRJCA001747) and PRJCA001746 (n=325, https://ngdc.cncb.ac.cn/bioproject/browse/PRJCA001746) were downloaded and screened for this study.3.The Cancer Genome Atlas (TCGA)-GBM: https://portal.gdc.cancer.gov/projects/TCGA-GBM. Whole-genome expression profile data in TPM format and corresponding clinical data were obtained via the R package TCGAbiolinks (version 2.25.0)0.4.UCSC Xena database: https://xenabrowser.net/datapages/. Integrated expression matrices of TCGA and Genotype-Tissue Expression (GTEx) data were downloaded for differential expression analysis between glioma and normal brain tissues.All analytical codes used in the current study are available from the corresponding authors on reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 5 keywords, 2 funders, 56 references.

Cite

This paper

Guo, J., Zhu, Z., Tong, N., Xu, D., Zhang, H., Lin, C., Wan, G., Wang, Y., Zhou, Q., & Xia, L. (2026). Single-cell profiling identifies a pro-tumoral VCAN positive macrophage subset and defines a prognostic signature in glioblastoma. Discover oncology, 17(1), 969. https://doi.org/10.1007/s12672-026-05166-y

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