In addition to antimicrobial activity, interferon (IFN)-γ also confers protective effects against tumorigenesis by inducing immune modulatory proteins in a Janus kinase (JAK)-signal transducers and activators of transcription (STAT)-mediated signaling pathway. For the feedback regulation of IFN-γ signaling, three families of proteins, the Src homology 2 domain-containing phosphatases (SHP2), the protein inhibitors of activated STATs, and the suppressors of cytokine signaling, inhibit specific and distinct aspects of IFN-γ-activated JAK-STAT. Regarding a variety of cancers may advance these regulations for avoiding the surveillance of IFN-γ, including cell growth suppression, cytotoxicity, and migration inhibition, it is speculated the oncogenic processes deregulate IFN-γ signaling. Epithelial-mesenchymal transition (EMT) is generally involved in cancer metastasis and invasion. The relative IFN-γ-hyporesponsive human lung adenocarcinoma AS2 and gastric adenocarcinoma AGS cells all showed mesenchemyal phenomenon. Chemically inducing EMT attenuated IFN-γ-induced signal transducers and activators of transcription 1/interferon regulatory factor 1 activation. Genetically engineering EMT-associated transcription factors, such as snail, slug, and hypoxia-inducible factor-1α, effectively retarded the signal transduction of IFN-γ. Transforming growth factor-β-induced EMT also retarded IFN-γ-induced major histocompatibility complex I and CD54 expression, cytotoxicity, and cell migration/invasion inhibition. Without changes on IFN-γ receptors, excessive activation of SHP2 in EMT cells primarily caused cellular hyporesponsiveness to IFN-γ signaling and cytotoxicity. These results imply EMT-associated SHP2 activation inhibits IFN-γ signaling, leading cancer cells escape from IFN-γ immunosurveillance.