Transforming growth factor-beta (TGF-beta) is abundantly expressed in malignant gliomas and is crucial for the tumor micromilieu. TGF-beta not only enhances migration and invasion of glioma cells but also inhibits an effective anti-glioma immune response. TGF-beta mediates its biologic effects through interactions with TGF-beta receptors (TbetaR)-I to -III. Binding of TGF-beta leads to the activation of an intracellular signaling cascade and subsequent phosphorylation of Sma and MAD-related proteins (SMAD). Soluble TGF-beta receptors (TbetaRs) abrogate the TGF-beta effect by competing for the binding of the ligand to its receptor. Here we used adenoviral gene transfer to express TbetaR-IIs and -IIIs in human glioma cell lines. TbetaR-IIs reduced SMAD2 phosphorylation and TGF-beta-dependent reporter activity. Furthermore, it enhanced glioma cell lysis by natural killer cells. TbetaR-IIIs alone were inactive in these assays, but enhanced the effects of TbetaR-IIs. Transduction of LN-308 cells with TbetaRs markedly delayed growth of intracerebral xenografts in nude mice in vivo. These data commend TbetaRs for possible experimental therapy of gliomas.