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<p>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 <i>SPP1</i> signaling: <i>SPP1</i> binding to <i>CD44</i> on tumor cells enhances their invasiveness, while its interaction with <i>CD47</i> on CD8⁺ T cells inhibits anti-tumor immunity. Transcriptional regulatory network analysis identified that <i>CDX2</i> and <i>MXI1</i> serve as key transcription factors modulating VCAN⁺ macrophage function and maintaining their specific polarization and homeostasis. Through machine learning, we identified seven hub genes—<i>C1QA</i>,<i> C1QC</i>,<i> C3</i>,<i> CCL4</i>,<i> CD44</i>,<i> SERPINE1</i>, and <i>TREM2</i> (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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月9日

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  • Jiaxin Guo,
  • Zhansheng Zhu,
  • Nanyang Tong,
  • Dingding Xu,
  • Huan Zhang,
  • Chenshi Lin,
  • Guiping Wan,
  • Yamei Wang,
  • Qingqing Zhou,
  • Liang Xia

摘要

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.