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<p>The tumor microenvironment (TME) is crucial for tumor formation and progression, but its specific impact on NF2-related tumors has not been well described. The aim of this study was to analyze the differences in the TME among NF2-related schwannomatosis (NF2-SWN) patients with different clinical phenotypes, explore the reasons for these differences, and identify targets for treatment while gaining a deeper understanding of the pathogenesis of the disease. 20 vestibular schwannomas (VSs) from 20 clinically diagnosed NF2-SWN patients, including 11 milder patients (Gardner) and 9 severe patients (Wishart), were analyzed. Single-cell sequencing, TCR sequencing, spatial transcriptomics analysis, multiplex immunofluorescence, immunohistochemistry, and cell experiments were performed to compare the TME of Gardner and Wishart and to elucidate the mechanisms underlying these differences. Our results revealed that NF2-VS consist of 12 significant cell subpopulations, with Gardner and Wishart presenting distinct TME. Wishart exhibited more pronounced immune suppression. Conversely, CD8<sup>+</sup> T cells from Gardner demonstrated potential for clonal proliferation. In macrophages, a subtype exhibited higher capacity of angiogenesis and high inflammatory cytokine activity was identified in Wishart, suggested its role in promoting tumor progression. Moreover, we found fibroblasts in Wishart showed excessive stromal deposition, potentially indicated the existence of immunologic barrier. Receptor‒ligand pair analysis revealed that Schwann cells in Wishart regulate immune cell activity via pleiotrophin (PTN), PTN positivity promotes anti-inflammatory cytokine activity, contributing to the formation of an immunosuppressive microenvironment to promote tumor progression. In summary, our study provides an in-depth analysis of the TME of NF2-VS, revealing the differences between Wishart and Gardner. Our study explains how Schwann cells influence the immune landscape to promote tumor development and clarifies the role of the TME in NF2-SWN progression, establishing a theoretical and experimental foundation for future immunotherapeutic strategies for NF2-SWN.</p>

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Single-cell and spatial transcriptomics analyses reveal tumor microenvironment–driven proliferation of NF2-associated vestibular schwannomas

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月9日

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  • Ying Wang,
  • Gang Xu,
  • Yuan Ren,
  • Tao Pan,
  • Ya Zhang,
  • Yanan Liu,
  • Zhijun Yang,
  • Zheng Zhao,
  • Peng Li,
  • Minjun Yan,
  • Chao Zhang,
  • Bo Wang,
  • Xin Ma,
  • Yongsheng Li,
  • Juan Xu,
  • Pinan Liu

摘要

The tumor microenvironment (TME) is crucial for tumor formation and progression, but its specific impact on NF2-related tumors has not been well described. The aim of this study was to analyze the differences in the TME among NF2-related schwannomatosis (NF2-SWN) patients with different clinical phenotypes, explore the reasons for these differences, and identify targets for treatment while gaining a deeper understanding of the pathogenesis of the disease. 20 vestibular schwannomas (VSs) from 20 clinically diagnosed NF2-SWN patients, including 11 milder patients (Gardner) and 9 severe patients (Wishart), were analyzed. Single-cell sequencing, TCR sequencing, spatial transcriptomics analysis, multiplex immunofluorescence, immunohistochemistry, and cell experiments were performed to compare the TME of Gardner and Wishart and to elucidate the mechanisms underlying these differences. Our results revealed that NF2-VS consist of 12 significant cell subpopulations, with Gardner and Wishart presenting distinct TME. Wishart exhibited more pronounced immune suppression. Conversely, CD8+ T cells from Gardner demonstrated potential for clonal proliferation. In macrophages, a subtype exhibited higher capacity of angiogenesis and high inflammatory cytokine activity was identified in Wishart, suggested its role in promoting tumor progression. Moreover, we found fibroblasts in Wishart showed excessive stromal deposition, potentially indicated the existence of immunologic barrier. Receptor‒ligand pair analysis revealed that Schwann cells in Wishart regulate immune cell activity via pleiotrophin (PTN), PTN positivity promotes anti-inflammatory cytokine activity, contributing to the formation of an immunosuppressive microenvironment to promote tumor progression. In summary, our study provides an in-depth analysis of the TME of NF2-VS, revealing the differences between Wishart and Gardner. Our study explains how Schwann cells influence the immune landscape to promote tumor development and clarifies the role of the TME in NF2-SWN progression, establishing a theoretical and experimental foundation for future immunotherapeutic strategies for NF2-SWN.