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The antimetastatic effect of the CD1d-binding glycolipid, α-galactosylceramide (α-GalCer), is mediated by NK1.1+T (NKT) cells; however, the mechanisms behind this process are poorly defined. Although it has been shown to involve NK cells and interferon-γ (IFN-γ) production, the way these factors collaborate to mediate effective tumor rejection and the importance of other factors characteristic of NKT cell and NK cell activation are unknown. Using gene-targeted mice and antibody treatments, the critical need for interleukin 12 (IL-12), IFN-γ, and NK cells has been shown in the antimetastatic activity of α-GalCer in the lungs and the liver. By contrast, in lung and liver metastasis models, cytotoxic molecules expressed by NK cells and NKT cells (perforin, Fas ligand, and tumor necrosis factor-related apoptosis-inducing ligand) and an NKT cell-secreted cytokine, IL-4, were not necessary for the antitumor activity of α-GalCer. Like IL-12, IL-18 was required for optimal serum IFN-γ induction and control of lung metastases by α-GalCer. IL-18 was unnecessary for α-GalCer–related suppression of liver metastases. Most importantly, after adoptive transfer of α-GalCer–reactive NKT cells or NK cells into NKT cell-deficient, IFN-γ–deficient, or RAG-1–deficient mice, it was demonstrated that the sequential production of IFN-γ by NKT cells and NK cells was absolutely required to reconstitute the antimetastatic activity of α-GalCer.