Authors
Leilei Tao, Fengbiao Guo, Xiaobei Liu, Xiao Zhao, Ya Xue, Weigang Bian, Jing Chen, Shaoyi Zhang, Bin Li
Published in
Oncogenesis. Jul 11, 2026. Epub Jul 11, 2026.
Abstract
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.
PMID:
42436128
Bibliographic data and abstract were imported from PubMed on 12 Jul 2026.
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