In a model of peritoneal metastasis in immune-competent mice, we show that nuclear factor (NF)-ÎºB inhibition in CT26 colon cancer cells prevents metastasis. NF-ÎºB inhibition, by stable overexpression of IÎºB-Î± super-repressor, induced differential polarization of co-cultured macrophages to an M1-like anti-tumour phenotype in vitro. NF-ÎºB-deficient cancer cell-conditioned media (CT26/IÎºB-Î± SR) induced interleukin (IL)-12 and nitric oxide (NO) synthaseÂ (inducible NO synthase (iNOS))Â expression in macrophages. Control cell (CT26/EV) conditioned media induced high levels of IL-10 and arginase in macrophages. In vivo, this effect translated to reduction in metastasis in mice injected with CT26/ IÎºB-Î± SR cellsÂ and was positively associated with increased CD8(+)CD44(+)CD62L(-)Â and CD4(+)CD44(+)CD62L(-)Â effector T cells. Furthermore, inhibition of NF-ÎºB activity induced high levels of NO in infiltrating immune cells and decreases in matrix metalloproteinase-9 expression, simultaneous with increases in tissue inhibitor of metalloproteinasesÂ 1 andÂ 2 within tumours. CT26/IÎºB-Î± SR tumours displayed increased pro-inflammatory gene expression, low levels of angiogenesis and extensive intratumoral apoptosis, consistent with the presence of an anti-tumour macrophage phenotype. Macrophage depletion reduced tumour size in CT26/EV-injected animals and increased tumour size in CT26/IÎºB-Î± SR cells compared withÂ untreated tumours. Our data demonstrate, for the first time, that an important implication of targeting tumour cell NF-ÎºB is skewing of macrophage polarization to an anti-tumour phenotype. This knowledge offers novel therapeutic opportunities for anticancer treatment.Oncogene advance online publication, 7 April 2014; doi:10.1038/onc.2014.86.