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<p>Tumor-associated macrophages (TAMs) constitute a pivotal cellular component within the intricate tumor microenvironment (TME). However, the relationship between the N6-methyladenosine (m6A) and metabolic pattern of TAMs remains poorly understood. Here we show that the m6A methyltransferase METTL3 is conspicuously downregulated in monocyte-derived macrophages from glioblastoma (GBM) patients. Conditional knockout of <i>Mettl3</i> in myeloid cells augments lipid metabolism and accelerates glioma progression. Furthermore, we found that METTL3 deficiency facilitates fatty acid synthase (FASN) expression, while compromising CD8<sup>+</sup> T cell response. Mechanistically, ISG15 is highly expressed in METTL3-deficient macrophages. ISG15 interacts with FASN and regulates FASN ISGylation and its stability through impeding FASN ubiquitination. Notably, the suppression of ISG15 in METTL3-deficient macrophages reverses the enhanced FASN expression and restores CD8<sup>+</sup> T cell functionality. Furthermore, we demonstrate that FASN knockout or FASN inhibitor treatment in myeloid cells abrogates the exaggerated tumor progression triggered by METTL3 knockout. Collectively, this study highlights the pivotal role of m6A in regulating macrophage metabolism and identifies potential targets in controlling GBM progression.</p>

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METTL3 abrogation promotes glioma progression through regulating the ISG15-FASN axis-mediated lipid metabolism in macrophages

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月8日

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  • Huilong Yin,
  • Xiaoyi Yu,
  • Chenglong Hu,
  • Yuhang Yang,
  • Mengke Wang,
  • Yating Xing,
  • Baile Zuo,
  • Chenxing Zhang,
  • Weilong Yang,
  • Yitong Li,
  • Zhuoya Yin,
  • Lijun Zhao,
  • Haijun Ma,
  • Yu Chen,
  • Chaowei Wang,
  • Zhuan Ju,
  • Bowen Liu,
  • Mingming Song,
  • Xiaoqing Chai,
  • Fudi Wang,
  • Angang Yang,
  • Rui Zhang

摘要

Tumor-associated macrophages (TAMs) constitute a pivotal cellular component within the intricate tumor microenvironment (TME). However, the relationship between the N6-methyladenosine (m6A) and metabolic pattern of TAMs remains poorly understood. Here we show that the m6A methyltransferase METTL3 is conspicuously downregulated in monocyte-derived macrophages from glioblastoma (GBM) patients. Conditional knockout of Mettl3 in myeloid cells augments lipid metabolism and accelerates glioma progression. Furthermore, we found that METTL3 deficiency facilitates fatty acid synthase (FASN) expression, while compromising CD8+ T cell response. Mechanistically, ISG15 is highly expressed in METTL3-deficient macrophages. ISG15 interacts with FASN and regulates FASN ISGylation and its stability through impeding FASN ubiquitination. Notably, the suppression of ISG15 in METTL3-deficient macrophages reverses the enhanced FASN expression and restores CD8+ T cell functionality. Furthermore, we demonstrate that FASN knockout or FASN inhibitor treatment in myeloid cells abrogates the exaggerated tumor progression triggered by METTL3 knockout. Collectively, this study highlights the pivotal role of m6A in regulating macrophage metabolism and identifies potential targets in controlling GBM progression.