Scholarlink

<p>Glioblastoma (GBM) acquires malignant traits through complex molecular adaptations that sustain immune evasion, often characterized by hypoxia and overexpression of the phagocytosis checkpoint CD47. However, the role of hypoxic drivers coordinating CD47-dependent immune evasion remains poorly defined. Here, we integrated single cell RNA sequencing and proteomic analysis to identify that insulin-like growth factor binding protein 2 (IGFBP2) was co-expressed with CD47 in hypoxic mesenchymal-like GBM subpopulations, synergistically promoting tumor progression and immune evasion. Mechanically, hypoxia induced IGFBP2 expression via HIF-2α-mediated transcriptional activation and further increased IGFBP2-positive exosome secretion through HIF-1α-dependent RAB3A upregulation. Moreover, IGFBP2 was predominantly localized on the exosome surface via integrin α5β1 and activated integrin/FAK/STAT3 signaling to enhance CD47 expression and inhibit macrophage phagocytosis. Clinically, serum exosomal IGFBP2 levels correlated with tumor grade and could serve as a diagnostic biomarker. Importantly, combinatorial blockade of IGFBP2 and CD47 synergistically suppressed tumor growth and prolonged survival in orthotopic GBM models. Together, our findings uncovered the hypoxia-exosomal IGFBP2-CD47 axis in GBM immune evasion and provided a compelling rationale for combination therapy to improve immunotherapy efficacy in GBM.</p><p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Targeting hypoxic exosomal IGFBP2 overcomes CD47-mediated immune evasion in glioblastoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月31日

查看全文
  • Yanhua Qi,
  • Rongrong Zhao,
  • Xinglong Zhang,
  • Huize Xia,
  • Ping Zhang,
  • Qingtong Wang,
  • Shulin Zhao,
  • Shaobo Wang,
  • Hongyu Zhao,
  • Xiaofan Guo,
  • Wei Qiu,
  • Boyan Li,
  • Ziwen Pan,
  • Jiawei Qiu,
  • Zijie Gao,
  • Chengwei Wang,
  • Haiquan Lu,
  • Gang Li,
  • Hao Xue

摘要

Glioblastoma (GBM) acquires malignant traits through complex molecular adaptations that sustain immune evasion, often characterized by hypoxia and overexpression of the phagocytosis checkpoint CD47. However, the role of hypoxic drivers coordinating CD47-dependent immune evasion remains poorly defined. Here, we integrated single cell RNA sequencing and proteomic analysis to identify that insulin-like growth factor binding protein 2 (IGFBP2) was co-expressed with CD47 in hypoxic mesenchymal-like GBM subpopulations, synergistically promoting tumor progression and immune evasion. Mechanically, hypoxia induced IGFBP2 expression via HIF-2α-mediated transcriptional activation and further increased IGFBP2-positive exosome secretion through HIF-1α-dependent RAB3A upregulation. Moreover, IGFBP2 was predominantly localized on the exosome surface via integrin α5β1 and activated integrin/FAK/STAT3 signaling to enhance CD47 expression and inhibit macrophage phagocytosis. Clinically, serum exosomal IGFBP2 levels correlated with tumor grade and could serve as a diagnostic biomarker. Importantly, combinatorial blockade of IGFBP2 and CD47 synergistically suppressed tumor growth and prolonged survival in orthotopic GBM models. Together, our findings uncovered the hypoxia-exosomal IGFBP2-CD47 axis in GBM immune evasion and provided a compelling rationale for combination therapy to improve immunotherapy efficacy in GBM.