Cutaneous melanoma is an increasingly frequent solid tumor that accounts for 80% of skin cancer-related deaths. Characterized by a complex and heterogeneous genetic background and a notorious functional plasticity, melanoma has shifted from a “black box” to a paradigm of how basic research can be successfully translated into significant improvements of patient prognosis [1]. Indeed, the identification of mutations in key oncogenic pathways (most frequently hyperactivating the BRAF>MEK signaling cascade) has paved the way to the development of genetically-targeted therapies [1]. Similarly, the discovery of intrinsic brakes to immune activation (i.e. involving the CTLA-4, PD1 or PD-L1 immune checkpoints) has also represented a clinical breakthrough in this disease [2]. Response rates, however are still incomplete [2]. Therefore, the field remains in need of a better understanding of the mechanistic basis underlying tumor progression and resistance to therapy.