In our study, we showed for the first time that NK cells stimulated with hypoxic lung cancer-derived EVs undergo tumor immune microenvironment editing, which is characterized by the up-regulation of pro-tumorigenesis cytokines (IL-6 and CCL2) and pro-angiogenic chemokines (VEGF, IL-8 and CXCL1) and those with immunosuppressive features (IL-10 and S100A8), as well as factors involved in the ECM remodeling cascade (MMP-1, MMP-7, MMP-14 and MMP-17). Here, MMP17 is linked to neoplasm.