In this study, we found that melanoma-associated fibroblasts decrease the susceptibility of melanoma tumor cells to NK-mediated lysis through the secretion of high levels of active MMPs, which reduce the NKG2D-dependent cytotoxic activity of NK cells by inducing the shedding of two NKG2D ligands, MICA/B, at the surface of tumor cells. Here, MICA is linked to melanoma.