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As the critical components of tumor microenvironment, cancer-associated fibroblasts (CAFs) support the development of various type of cancers, including laryngeal squamous cell carcinoma (LSCC), but the detailed molecular mechanisms by which cancer-associated fibroblasts interact with LSCC cells to facilitate its progression have not been fully uncovered. In the present study, by analyzing the contents from normal fibroblasts (NFs) and cancer-associated fibroblasts-derived extracellular vesicles (EVs) with Real-Time qPCR analysis, we found that the tumor-initiating LncRNA TUC338 was significantly upregulated in the cancer-associated fibroblasts-derived extracellular vesicles, compared to the normal fibroblasts-secreted extracellular vesicles. Further experiments confirmed that cancer-associated fibroblasts-derived extracellular vesicles promoted cell proliferation, colony formation abilities, epithelial-mesenchymal transition (EMT) and tumorigenesis of LSCC cells via delivering LncRNA TUC338. The mechanical experiments verified that LncRNA TUC338 was stabilized by METTL3/YTHDF1-mediated N6-methyladenosine (m6A) modifications, and elevated LncRNA TUC338 sponged miR-8485 to upregulate chromobox homolog 2 (CBX2) in LSCC cells in a competing endogenous RNA mechanisms-dependent manner. Moreover, our rescue experiments evidenced that cancer-associated fibroblasts-derived LncRNA TUC338-containing extracellular vesicles-induced supportive effects in LSCC aggressiveness were all abrogated by overexpressing miR-8485 and silencing CBX2. Collectively, this study is the first to identify a novel m6A/LncRNA TUC338/miR-8485/CBX2 axis in CAFs-EVs-mediated LSCC development, and to show its potential as a diagnostic biomarker for LSCC. • CAFs-derived extracellular vesicles enhanced cancer aggressiveness of LSCC via delivering TUC338. • METTL3/YTHDF1-mediated m6A modifications are essential for sustaining the stability and expression of TUC338. • TUC338 upregulated CBX2 via sponging miR-8485 in a ceRNA-dependent manner. • TUC338-EVs promoted LSCC progression through modulating the miR-8485/CBX2 axis. [ABSTRACT FROM AUTHOR]