Aberrant expression of the T-box transcription factor brachyury in human carcinomas drives the phenomenon of epithelial-mesenchymal transition (EMT), a phenotypic modulation that facilitates tumor dissemination and resistance to conventional anti-neoplastic therapies. Hamilton and colleagues show that acquisition of a mesenchymal-like phenotype could also significantly reduce the susceptibility of cancer cells to lysis by both antigen-specific T cells and natural killer cells. This defect was observed even in the presence of a stable engagement between the immune effector cells and the tumor cells, as demonstrated by the effective polar actin polymerization observed at the interacting surface area. The phenomenon of immune resistance of mesenchymal-like cells was correlated to their decreased levels of cell cycle kinase CDK1, a defect that could be countered by treatment with a specific inhibitor of WEE1. For details, see article by Hamilton and colleagues on page 2510.