Tumor infiltrating lymphocytes (TILs) are frequently detected in a variety of malignancies, including gastric cancer (GC). TILs are known to produce high level of interferon-gamma (IFN-γ) in GC, but fail to suppress tumor growth. We have previously shown that Rhotekin (RTKN), the gene encoding the Rho effector RTKN, is overexpressed in human GC, and its expression is correlated with disease progression. In this study, we show that RTKN expression efficiently blocks IFN-γ-mediated anti-growth and immunologic responses, suggesting a role of RTKN in attenuating tumor immunosurveillance during GC pathogenesis. We show that RTKN attenuates STAT1 phosphorylation in response to IFN-γ, and confers increased resistance to IFN-γ-mediated growth suppression in GC cells through inhibiting the expression of STAT1-dependent downstream target genes, including cyclin-dependent kinase inhibitor p21 and antiapoptotic genes BCL-2 and BCL-xL. Conversely, elimination of RTKN expression by knockdown approach facilitates IFN-γ-mediated STAT1 phosphorylation and promotes IFN-γ-mediated growth arrest and apoptosis. We further show that RTKN-mediated inhibition of STAT1 phosphorylation can be reversed by the treatment of sodium orthovanadate, a tyrosine phosphatase inhibitor, suggesting the involvement of tyrosine phosphatases in RTKN-mediated process. In support, our data show that RTKN suppresses IFN-γ-mediated STAT1 phosphorylation partly through facilitating the interactions of SHP2 and STAT1. In summary, our data suggest that RTKN overexpression confers growth advantages to GC by evading immunosurveillance through suppression of IFN-γ-mediated anti-tumor activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4435. doi:1538-7445.AM2012-4435