Prolonged sun exposure combined with other multi-factorial cues can transform skin’s melanocytes into melanoma cells characterized by uncontrolled proliferation. If not removed on time, melanoma cells can quickly spread into other tissues and form lethal secondary tumors called metastasis. Several anti-melanoma drugs have been developed in the last decade, in particular immunotherapy to help our natural protective barrier or immune system to eradicate cancer cells. Immune system is a group of diverse cells able to activate biological responses to eliminate foreign organisms (i.e., viruses) or abnormal cells including cancer cells. However, melanoma cells can modify the expression of genes that confer them special “identities” allowing them to become invisible to the immune system. Therefore, a better characterization of these identities remains essential to define new therapeutic targets. Using complex bioinformatic analyses, we compared the expression of several genes among different tumors and normal tissues. Surprisingly, we identified a new gene named HOXD13 almost exclusively expressed in melanoma cells of patients non responsive to immunotherapy. Through genetically modified mice able to develop melanoma, we observed that HOXD13 activation confers to melanoma cells an invisible identity to the immune system. Using other molecular techniques, we demonstrate that HOXD13 activates two other genes named CD73 and NGFR which we suspect being the main actors of immune invisibility. Altogether, our studies will reveal whether HOXD13/CD73/NGFR axes inhibition could make melanoma cells more visible to the immune system and improving immunotherapy response with a direct relevance for the patients.