CD1-deficient mice reject established, disseminated 4T1 metastatic mammary cancer and survive indefinitely if their primary mammary tumors are surgically removed. This highly effective immune surveillance is due to three interacting mechanisms: (a) the generation of inducible nitric oxide synthase (iNOS)–producing M1 macrophages that are tumoricidal for 4T1 tumor cells; (b) a rapid decrease in myeloid-derived Gr1⁺CD11b⁺ suppressor cells that are elevated and down-regulate the CD3ζ chain when primary tumor is present and that suppress T cells by producing arginase; and (c) production of activated lymphocytes. Macrophages from wild-type BALB/c mice are polarized by interleukin-13 (IL-13) towards a tumor-promoting M2 phenotype, thereby inhibiting the generation of tumoricidal M1 macrophages. In contrast, CD1^−/− mice, which are deficient for IL-13 because they lack IL-13–producting NKT cells, generate M1 macrophages that are cytotoxic for 4T1 via the production of nitric oxide. Although tumoricidal macrophages are a necessary component of immune surveillance in CD1^−/− mice, they alone are not sufficient for tumor resistance because IL-4Rα^−/− mice have M1 macrophages and retain high levels of myeloid suppressor cells after surgery; in addition, they are susceptible to 4T1 metastatic disease. These results show that effective immune surveillance against established metastatic disease is negatively regulated by IL-13 and requires the induction of tumoricidal M1 macrophages and lymphocytes combined with a reduction in tumor-induced myeloid suppressor cells. (Cancer Res 2005; 65(24): 11743-51)