We provide evidence that ISG15-silenced tumors grow rapidly compared to ISG15 overexpressing tumors in nude mice, that recombinant free ISG15 inhibits tumor growth when added extracellularly and induce intratumor infiltration of NK cells in nude mice, and that intracellular free ISG15 enhances 26S proteasome-dependent surface expression of MHC class I complexes on breast cancer cells. This evidence concerns the gene ISG15 and breast carcinoma.