CD1d-restricted natural killer T (NKT) cells are one of immunoregulatory cells. NKT cells can be specifically activated by a synthetic glycolipid, α-galactosylceramide (α-GalCer). Using some glycolipids such as α-GalCer, it is expected to develop a new NKT cell-mediated therapeutic strategy against cancer. However, it is known that, in human cancer patients, NKT cells express a degree of hyporesponsiveness to α-GalCer. For example, we have reported that, in gastrointestinal cancer patients, NKT cell proliferation and cytokine production were impaired. We have further examined the mechanism by which hyporesponsiveness to α-GalCer can be induced using cancer-bearing mice. In the animal study, α-GalCer-induced NKT cell expansion, cytokine production, cytotoxicity, and anti-metastatic 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. We found that CD11b⁺ Gr-1⁺ cells were particularly increased in cancer-bearing mice and were necessary and sufficient for the suppression of NKT cells to α-GalCer. We also found that the increased CD11b⁺ Gr-1⁺ cells suppressed NKT cell function in a nitric oxide-mediated fashion. To reduce the population of CD11b⁺ Gr-1⁺ cells, we administered a retinoic acid to cancer-bearing mice. This treatment significantly reduced the population of CD11b⁺ Gr-1⁺ cells and effectively restored α-GalCer-induced NKT cell responses. These results demonstrate a novel feature of NKT cell function in cancer, and suggest a new strategy to enhance NKT cell-mediated anti-cancer immune responses by suppressing CD11b⁺ Gr-1⁺ cell functions.