HIF-2α accumulation in human monocytes upon transfer of hypoxia-associated miRNAs via plasma-derived small extracellular vesicles from head and neck cancer patients

Hypoxia is an important hallmark of the tumor microenvironment (TME) in solid tumors and is closely associated with resistance to radiotherapy and a poorer clinical outcome. Tumor-associated plasma-derived small extracellular vesicles (sEVs) have gained increasing attention as an important regulatory TME component for tumor progression and immune evasion. This study aimed to investigate the involvement of plasma-derived sEVs from head and neck squamous cell carcinoma (HNSCC) patients in the systemic regulation of hypoxia-related molecular pathways in circulating immune cells. Plasma-derived sEVs of healthy donors (HDs) and HNSCC patients were isolated and evaluated for morphology, size, miRNA cargo composition, and their influence on monocyte characteristics. Transfer of plasma-derived sEVs from HNSCC patients stimulated increased levels of checkpoint molecule PD-L1 and chemokine CXCL4 secretion. An accumulation of hypoxia-inducible factor (HIF)-2α was associated with hypoxia-regulating miRNAs in sEVs from HNSCC patients. This provides new insights into a proposed tumor-associated systemic sEV-miRNA-mediated hypoxia transfer.