The picture depicts the biotechnological approach used to obtain personalized RNA-based vaccines for melanoma treatment (circle). The whole pattern of mutations inside the tumor mass, so-called the “mutanome”, is obtained by comparing DNA and RNA from both blood and bioptic sample. Based on the results, 10 neoantigens are selected for each patient if predicted to have high-affinity binding to the endogenous MHC class II and class-I molecules. The nucleic acid sequences are then engineered to produce RNAs encoding peptides corresponding to the selected neoantigens and injected into inguinal lymph nodes, where they will be translated into peptides, associated to MHC molecules and presented to T cells. This vaccination approach may work in synergy with checkpoint inhibitor-based immunotherapies (central panel), which may cooperate in unbreaking the response to vaccine neoantigens.