Tumor-derived fucosylated exosomes (FUC-Exo) have emerged as critical contributors to cancer progression, yet the roles and mechanisms of exosomal fucosylated miRNAs in esophageal squamous cell carcinoma (ESCC) remain largely unexplored. By employing lentil lectin (LCA)-coated magnetic beads to isolate FUC-Exo, followed by small RNA sequencing and RT-qPCR, miR-6842-3p was identified as a novel biomarker for ESCC. Functional studies in vitro and in vivo demonstrated its oncogenic and pro-angiogenic effects. Mechanistic investigations using dual-luciferase reporter assays, ChIP-qPCR, western blotting, and rescue experiments revealed the underlying pathways. miR-6842-3p is markedly elevated in ESCC tissues and serum FUC-Exo, correlates with advanced disease stages, poorer prognosis, and holds promise as an early diagnostic marker. Functioning as an oncogene, miR-6842-3p enhances tumor growth, metastasis, and angiogenesis. Upon uptake by HUVECs, tumor-derived fucosylated exosomal miR-6842-3p suppresses PTEN, leading to AKT and mTOR phosphorylation, subsequent downregulation of IRF1, decreased CXCL10 expression, and ultimately enhanced angiogenesis. These findings establish miR-6842-3p as a pivotal regulator of ESCC progression and angiogenesis, with fucosylated exosomal miR-6842-3p acting through the PTEN/AKT/mTOR/IRF1/CXCL10 axis, underscoring its potential as both a biomarker and therapeutic target in ESCC.
