Hiltonol+++ efficiently suppressed lung cancer migration and invasion. The effects of Hiltonol alone or polyI:C alone or their respective combinatorial treatments (with anti-IL6+stattic+AG490) on metastatic potential in lung cancer were examined by migration assay: (A) A549 (B) H292 (C) H1299 and (D) H358 cells. The rate of migration was quantified as % gap closure normalized to corresponding 0 h time point DMSO-treated controls. Compared with polyI:C+++ (polyI:C+anti-IL6+stattic+AG490)-treated cells, the Hiltonol+++ (Hiltonol+anti-IL6+stattic+AG490)-treated cells displayed significant delay in migration, particularly for A549, H292, and H358 cells. In earlier time points (12 h or 16 h), the LSD value in A549, H292, H1299, and H358 are 1.876, 2.048, 1.697, and 2.247, respectively. In later time points (either 24 h or 36 h), the LSD value in A549, H292, H1299, and H358 are 2.17, 1.724, 0.83, and 2.799, respectively. **, p < 0.01; ***, p < 0.001. (E) shows cell invasion of these three cell lines. PolyI:C+++ reduced invasion of A549 and H358 by 30% and 12%, respectively, whereas Hiltonol+++ further abrogated cell invasion of A549, H292, and H358 cells by 57%, 36%, and 76%, respectively. ***, p < 0.001. The LSD value in A549, H292, and H358 are 10.187, 9.967, and 11.004, respectively.