The decreased antitumor immune response significantly contributes to the progression of glioma. To evaluate whether the antitumor immunity is restored by stable co-expression of IL-18 and Fas receptor, we retrovirally introduced these two genes into rat C6 glioma cells. We found that IL-18-transduced glioma cells secreted IL-18 and induced PBMC IFN-gamma production in vitro. We also found that Fas-transduced glioma cells were susceptible to Fas-mediated apoptosis. In vivo, we found that IL-18 expression and Fas expression synergistically inhibited C6 cell tumorigenesis with the glioma cells being subcutaneously injected in rat flank. Furthermore, we found that co-expression of IL-18 and Fas also produced a marked survival advantage with the rats being intracerebrally implanted with the glioma cells. Finally, we demonstrated that FasL-dependent PBMC cytotoxicity participated in the anti-glioma immunity induced by IL-18 and Fas expression. Taken together, these findings demonstrate that increasing IL-18 production in tumor microenvironment and prompting functional Fas receptor expression of tumor cells could enhance FasL-dependent cytotoxic antitumor immunity. (C) 2004 Elsevier Inc. All rights reserved.