CD1d-restricted natural killer T (NKT) cells are a potential therapeutic target for cancer, for which several clinical trials have already been reported. NKT cells are specifically activated by a synthetic glycolipid, α-galactosylceramide (α-GalCer). However, it is known that, in human cancer patients, NKT cells express a degree of hyporesponsiveness to α-GalCer. In this study, we have examined the mechanism by which hyporesponsiveness to α-GalCer can be induced. In cancer-bearing mice, α-GalCer-induced NKT cell expansion, cytokine production, cytotoxicity, and antimetastatic effect in vivo were all significantly impaired. In fact, α-GalCer could eliminate metastatic disease in naive animals but failed to protect cancer-bearing mice. CD11b⁺ Gr-1⁺ cells were particularly increased in cancer-bearing mice and were necessary and sufficient for the suppression of the α-GalCer response in a nitric oxide–mediated fashion. Administration of a retinoic acid to cancer-bearing mice reduced the population of CD11b⁺ Gr-1⁺ cells and effectively restored α-GalCer-induced protection. These results show a novel feature of NKT cell function in cancer. Furthermore, our data suggest a new strategy to enhance NKT cell-mediated anticancer immune responses by suppressing CD11b⁺ Gr-1⁺ cell functions. (Cancer Res 2006; 66(23): 11441-6)