Fig. 2

HNC-derived EVs in the cancer-to-stroma communication network. HNC-derived EVs can deliver various oncogenic proteins and noncoding RNA molecules to regulate surrounding cells. When the tumor cells are in hypoxic conditions or receive chemoradiotherapy, the gate of EV release can be opened, promoting the proliferation, migration and invasion, chemoradiotherapy resistance of cancer cells via EMT or other pathways. Endothelial cells actively absorb HNC-derived EVs, produce a variety of pro-angiogenic factors, induce angiogenesis, increase vascular permeability, and ultimately provide a venue for the distant metastasis of tumor cells. HNCs can package their "undesirable" substances (Cav-1 and Dsg-2) and assist the transformation of fibroblasts into CAFs. HNC-derived EVs can also regulate tumor immune responses. EVs can inhibit T-cell proliferation and Th1 and Th17 differentiation. Tregs are more susceptible to regulation by exosomal-miRNA-24-3p, which induces tumor immune tolerance. EVs activate T-cell surface receptors (FasL and MHC-I) to mediate the apoptosis of CD8+ T cells or via protein Gal-1-induced CD8+ T cells to display a suppressor phenotype. EVs induce the polarization of THP-1 to tumor-associated macrophages M2. Under certain conditions, exosomal NAP-1 could increase the cytotoxic activity of NK cells. HNC-derived EVs can mediate cancer-to-stroma communication to construct a premetastatic niche