CAF-derived extracellular vesicle-associated LINC02420 links stromal communication to HIF1A-dependent glycolytic regulation in head and neck cancer

Tumor metabolic reprogramming is a hallmark of aggressive head and neck Cancer (HNC), with enhanced glycolytic activity representing a major metabolic phenotype. However, how stromal signals in the tumor microenvironment (TME) sustain this process remains unclear. Here, we identify LINC02420 as a long noncoding RNA (lncRNA) enriched in cancer-associated fibroblast-derived extracellular vesicles (CAF-EVs). CAFs delivered LINC02420 to recipient HNC cells through EVs. LINC02420 increased lactate production and cell migration in HNC cells, and enhanced glucose-derived labeling of glycolytic intermediates and lactate. Reducing LINC02420 in donor CAFs attenuated the glycolysis-enhancing and pro-malignant effects of CAF-EVs. Mechanistically, CAF-EV-associated LINC02420 binds AEG-1, encoded by MTDH, and stabilizes AEG-1 protein. Stabilized AEG-1 enhances NF-κB signaling and p65 nuclear translocation. It also supports formation of an AEG-1-p65-p300 transcriptional complex at the HIF1A promoter, thereby increasing HIF1A transcription and glycolysis-related gene expression. In vivo, CAF-derived LINC02420 promoted HNC tumor growth. Clinically, LINC02420 was elevated in HNC tissues and plasma-derived EVs, and high tumor LINC02420 expression was associated with poorer overall survival. These findings identify a CAF-EV-associated lncRNA mechanism linking TME-derived stromal communication to HIF1A-dependent glycolytic regulation and support plasma EV-associated LINC02420 as a potential circulating biomarker for monitoring HNC progression.