Tumor metastasis accounts for most tumor-associated mortality and is closely related with stromal fibroblasts in the tumor microenvironment. It was reported that fibroblasts promoted tumor metastasis through directly leading tumor cell invasion; however, inflammatory microenvironment in the growing tumor may influence the outcome. Here, we found that the cytokine IFN gamma, a key immune mediator secreted by T cells, could alter mouse lung tumor associated fibroblast-leading LLC tumor cell invasion in Matrigel. The motility of fibroblasts and adhesion with tumor cells were dramatically impaired upon IFN gamma stimulation. We further found that IFN gamma reduced the expression of N-cadherin on the surface of fibroblasts through upregulating SMAD7 and suppressing the downstream SMAD2 phosphorylation. Ncadherin was essential for fibroblast motility and adhesions with tumor cells. Moreover, fibroblasts could promote tumor progression and the deficiency of IFN gamma R signaling in fibroblasts reduced liver metastasis of LLC tumor in vivo. Collectively, our results demonstrate that IFN gamma inhibits fibroblast-leading tumor cell invasion by inhibiting the motility of fibroblasts and their adhesion with tumor cells. The findings indicate that inflammatory cytokines in the tumor microenvironment may regulate the fibroblast associated tumor metastasis. (C) 2019 Elsevier Inc. All rights reserved.