PURPOSE: The ability of natural killer (NK) cells to lyse allogeneic targets, without the need for explicit matching or priming, makes them an attractive platform for cell-based immunotherapy. Umbilical cord blood is a practical source for generating banks of such third party NK cells for "off the shelf" cell therapy applications. NK cells are highly cytolytic, and their potent antitumor effects can be rapidly triggered by a lack of HLA expression on interacting target cells, as is the case for a majority of solid tumors, including neuroblastoma. Neuroblastoma is a leading cause of pediatric cancer-related deaths and an ideal candidate for NK cell therapy. However, the antitumor efficacy of NK cells is limited by immunosuppressive cytokines in the tumor microenvironment, such as TGFbeta, which impair NK cell function and survival. EXPERIMENTAL DESIGN: To overcome this, we genetically modified NK cells to express variant TGFbeta receptors which couple a mutant TGFbeta dominant negative receptor to NK-specific activating domains. We hypothesized that with these engineered receptors, inhibitory TGFbeta signals are effectively converted to activating signals. RESULTS: Modified NK cells exhibited higher cytotoxic activity against neuroblastoma in a TGFbeta-rich environment in vitro and superior progression-free survival in vivo, as compared to their unmodified controls. CONCLUSIONS: Our results support the development of "off the shelf" gene-modified NK cells, that overcome TGFbeta-mediated immune evasion, in patients with neuroblastoma and other TGFbeta-secreting malignancies.