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<p>Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment that can drive cancer progression and immune evasion. Here, we identify a novel pathway in which lactate produced by lung adenocarcinoma (LUAD) cells activates normal fibroblasts into CAFs, inducing high expression of microRNA miR-214-5p. The CAFs secrete miR-214-5p via exosomes, which in turn polarizes tumor-associated macrophages (TAMs) toward the immunosuppressive M2 phenotype. Mechanistically, exosomal miR-214-5p targets the transcriptional repressor BHLHE41 in macrophages, relieving its inhibition on M2-polarization genes. We further demonstrate that lactate accumulation epigenetically upregulates miR-214-5p in CAFs by increasing histone H3 lysine 9 lactylation (H3K9la) at the DNM3OS/miR-214 gene locus, independently of the lactate receptor GPR81. Lactate also enhances the loading of miR-214-5p into exosomes by inducing lactylation of the RNA-binding protein YBX1, which binds miR-214-5p and facilitates its exosomal export. In a mouse co-implantation model of LUAD, pharmacological blockade of tumor lactate production (LDH inhibition) reduced CAF activation, TAM M2 polarization, miR-214-5p levels, and tumor growth. Our findings uncover a lactate-driven CAF-TAM signaling axis via exosomal miR-214-5p, highlighting potential therapeutic targets to counteract tumor immune evasion in lung adenocarcinoma.</p>

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Lung adenocarcinoma cell-derived lactate activates CAFs to promote macrophage M2 polarization via exosomal miR-214-5p

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月11日

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  • Leilei Tao,
  • Fengbiao Guo,
  • Xiaobei Liu,
  • Xiao Zhao,
  • Ya Xue,
  • Weigang Bian,
  • Jing Chen,
  • Shaoyi Zhang,
  • Bin Li

摘要

Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment that can drive cancer progression and immune evasion. Here, we identify a novel pathway in which lactate produced by lung adenocarcinoma (LUAD) cells activates normal fibroblasts into CAFs, inducing high expression of microRNA miR-214-5p. The CAFs secrete miR-214-5p via exosomes, which in turn polarizes tumor-associated macrophages (TAMs) toward the immunosuppressive M2 phenotype. Mechanistically, exosomal miR-214-5p targets the transcriptional repressor BHLHE41 in macrophages, relieving its inhibition on M2-polarization genes. We further demonstrate that lactate accumulation epigenetically upregulates miR-214-5p in CAFs by increasing histone H3 lysine 9 lactylation (H3K9la) at the DNM3OS/miR-214 gene locus, independently of the lactate receptor GPR81. Lactate also enhances the loading of miR-214-5p into exosomes by inducing lactylation of the RNA-binding protein YBX1, which binds miR-214-5p and facilitates its exosomal export. In a mouse co-implantation model of LUAD, pharmacological blockade of tumor lactate production (LDH inhibition) reduced CAF activation, TAM M2 polarization, miR-214-5p levels, and tumor growth. Our findings uncover a lactate-driven CAF-TAM signaling axis via exosomal miR-214-5p, highlighting potential therapeutic targets to counteract tumor immune evasion in lung adenocarcinoma.