Furthermore, in patients with a progressive disease, we found a strong enrichment of cases with a mutation in at least one of the genes BRAF, EGFR, PTEN, TP53 or CDKN2A. Nevertheless, prospective studies are urgently needed to learn more about potential ICI resistance mechanisms, and further effort should be made to introduce targeted therapies beyond BRAF, MEK or KIT inhibitors, such as MYC or MDM2 inhibitors for metastasized melanoma. Here, PTEN is linked to melanoma.