Non-small cell lung cancer (NSCLC) is a serious threat for human health and life. Natural killer (NK) cell-based immunotherapy is a promising anti-tumor strategy in various cancers including NSCLC. Emerging microRNA (miRNA) has been identified as vital regulators in NK cell-mediated immunosurveillance process. MicroRNA-130a (miR-130a) level and signal transducers and activators of transcription 3 (STAT3) mRNA level was measured by RT-qPCR assay. STAT3 protein level was determined by western blot assay. IFN-gamma and TNF-alpha secretion was examined by corresponding ELISA kits. NK cell cytotoxicity was assessed by lactate dehydrogenase (LDH) assay. The interaction between miR-130a and STAT3 was explored by bioinformatics analysis, luciferase reporter assay and RNA immunoprecipitation (RIP) assay. We found that MiR-130a level was notably reduced and STAT3 expression was dramatically increased in primary NK cells isolated from NSCLC patients. But, miR-130a was highly expressed and STAT3 was low expressed in IL-2-activated NK-92 cells. Functional analysis revealed that miR-130a overexpression potentiated killing ability of NK cells against A549 cells. Further investigations unveiled that STAT3 was a target of miR-130a and STAT3 overexpression abrogated miR-130a-induced improvement in killing activity of NK cells against NSCLC cells. In conclusion, MiR-130a improved the killing capacity of NK cells against NSCLC cells by targeting STAT3, laying a foundation for future studies on the roles and molecular basis of miR-130a in NK cell-based immunotherapy against various cancers. (C) 2019 Elsevier Inc. All rights reserved.