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Through single-cell RNA sequencing (scRNA-seq) and bioinformatic analysis, we delineated macrophage heterogeneity within the GBM TME and identified a distinct VCAN\u207a 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\u207a macrophages displayed a distinct polarization state driven by tumor necrosis factor-\u03b1 (TNF-\u03b1), contributing to both a pro-inflammatory and an immunosuppressive TME. CellChat analysis demonstrated their pivotal role in intercellular communication\u2014predominantly mediating crosstalk with GBM tumor cells, endothelial cells, and CD8\u207a T cells via\n                    <jats:italic>SPP1<\/jats:italic>\n                    signaling:\n                    <jats:italic>SPP1<\/jats:italic>\n                    binding to\n                    <jats:italic>CD44<\/jats:italic>\n                    on tumor cells enhances their invasiveness, while its interaction with\n                    <jats:italic>CD47<\/jats:italic>\n                    on CD8\u207a T cells inhibits anti-tumor immunity. Transcriptional regulatory network analysis identified that\n                    <jats:italic>CDX2<\/jats:italic>\n                    and\n                    <jats:italic>MXI1<\/jats:italic>\n                    serve as key transcription factors modulating VCAN\u207a macrophage function and maintaining their specific polarization and homeostasis. Through machine learning, we identified seven hub genes\u2014\n                    <jats:italic>C1QA<\/jats:italic>\n                    ,\n                    <jats:italic>C1QC<\/jats:italic>\n                    ,\n                    <jats:italic>C3<\/jats:italic>\n                    ,\n                    <jats:italic>CCL4<\/jats:italic>\n                    ,\n                    <jats:italic>CD44<\/jats:italic>\n                    ,\n                    <jats:italic>SERPINE1<\/jats:italic>\n                    , and\n                    <jats:italic>TREM2<\/jats:italic>\n                    (all highly expressed in VCAN\u207a macrophages and involved in their polarization or intercellular communication)\u2014and constructed an effective GBM prognostic model (AUC\u2009=\u20090.83 in validation cohort), underscoring their roles in immune regulation, extracellular matrix remodeling, and VCAN\u207a macrophage-mediated tumor progression. Further studies with larger cohorts and functional validation will clarify this subpopulation\u2019s therapeutic potential and spatial distribution patterns.\n                  <\/jats:p>","DOI":"10.1007\/s12672-026-05166-y","type":"journal-article","created":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T12:43:39Z","timestamp":1778330619000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Single-cell profiling identifies a pro-tumoral VCAN positive macrophage subset and defines a prognostic signature in glioblastoma"],"prefix":"10.1007","volume":"17","author":[{"given":"Jiaxin","family":"Guo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhansheng","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanyang","family":"Tong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dingding","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenshi","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guiping","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingqing","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,9]]},"reference":[{"key":"5166_CR1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14102412","author":"S Grochans","year":"2022","unstructured":"Grochans S, Cybulska AM, Siminska D, Korbecki J, Kojder K, Chlubek D, et al. 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All data were acquired in compliance with the open access policies and ethical guidelines of the original data repositories. No direct human or animal experiments were conducted in this research, and thus formal ethical approval from an institutional review board was not required. All analytical procedures were performed in accordance with the Declaration of Helsinki and the relevant ethical regulations for bioinformatics research involving human genomic data. This study utilized de-identified, publicly available data without any personally identifiable information of the participants. The original datasets included in this research were collected and published with written informed consent from all participants by the original data curation teams. As no new human subjects were recruited and no direct interactions with participants were involved in this study, additional informed consent to participate is not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All data used in this study are from public and open-access databases, and the original data have been published with the consent of the participants by the original research groups. This study only conducted secondary analysis of the existing de-identified data, and no unpublished individual clinical, biological or identifying information is disclosed in the manuscript. Therefore, additional consent to publish is not required for the present study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"969"}}