SNHG16-loaded extracellular vesicles from hypoxic NSCLC cells drive M2 macrophage polarization to enhance cancer aggressiveness.

Hypoxia plays a critical role in regulating the progression of non-small cell lung cancer (NSCLC) by modulating the tumor immune microenvironment (TIME). Tumor-associated macrophages (TAMs), important components of TIME, can be regulated by hypoxic conditions. Unfortunately, the molecular mechanisms by which hypoxia regulates TAMs in TIME to affect NSCLC progression has not been fully delineated. The present study evidenced that hypoxia-stimulated NSCLC cells secreted extracellular vesicles (EVs) were featured with highly expressed small nucleolar RNA host gene 16 (SNHG16), and SNHG16-containing EVs (SNHG16-EVs) synergistically promoted cell proliferation, epithelial-mesenchymal transition (EMT), and cancer stem cell (CSC) properties in NSCLC cells, and induced M2-polarization of macrophages in THP-1 cells through delivering SNHG16. Notably, M2-polarized macrophages were capable of enhancing cancer aggressiveness in NSCLC cells through secreting tumor-initiating cytokines, including interleukin-10 (IL-10), transforming growth factor β (TGF-β), and vascular endothelial-derived growth factor (VEGF). Mechanistically, it was found that SNHG16 sponged miR-132-3p to positively regulate its downstream target, kinesin family member 5 A (KIF5A), via a competing endogenous RNA (ceRNA) mechanism-dependent manner. Rescue experiments confirmed that SNHG16-EVs induced NSCLC progression and M2 polarization of THP-1 cells were all reversed by overexpressing miR-132-3p and silencing KIF5A. Collectively, hypoxia-stimulated NSCLC cells transferred SNHG16-containing EVs to promote cancer aggressiveness and M2-polarized macrophages in NSCLC through modulating the downstream miR-132-3p/KIF5A axis, and this study verified that targeting SNHG16-EVs may be a novel strategy to hamper NSCLC progression via modulating TME.