IL-33 is a member of IL-I superfamily that drives production of Th2-related cytokines. Recently, accumulating evidence suggest an involvement of IL-33 in carcinogenesis. Herein, we determine a close correlation of IL-33 expression and cancer progress in patients with non-small-cell lung cancer (NSCLC). Overexpression of IL-33 by transfection with IL-33 expression vector enhances NSCLC outgrowth and metastasis, while genetic knockdown of IL-33 by transfection with IL-33 shRNA limits NSCLC progression. In consistent, IL-33 stimulation of NSCLC cells leads to robust NSCLC outgrowth and metastasis in vitro and in vivo. Mechanically, IL-33-triggered NSCLC progression relies on ST2 receptor and could be abrogated by ST2 blockade.IL-33/ST2 pathway up-regulates membrane glucose transporter 1 (GLUTI) on NSCLC cells, enhancing their glucose uptake and glycolysis. Accordingly, interfering GLUT1 expression dampens IL-33-enhanced glucose uptake and glycolysis in NSCLC cells, thereby abrogates IL-33-induced NSCLC outgrowth and metastasis. In essence, these findings derived from patients' NSCLC cells uncover a new function of IL-33 in NSCLC pathogenesis and identify GLUT1 as a novel target of IL-33 signaling. Block IL-33 is a promising therapeutic strategy to limit NSCLC glycolysis and tumor progression in clinical practice. (C) 2016 Elsevier Inc. All rights reserved.