Background: Immunotherapies blocking the interaction of CTLA-4 or Programmed Death 1 (PD-1) with their ligands are the standard of care for advanced MEL although many pts fail to benefit from immunotherapy. Herein, we seek to identify epigenetic and genetic signatures associated with lack of response in patients treated with immunotherapy.Methods: We performed whole exome sequencing of 580 cancer-related genes and whole-genome DNA methylation arrays targeting > 850k CpG sites covering promoters, enhancers, and transcription factor sites in 28 MEL samples from patients treated with PD-1 +/- CTLA-4 inhibitors. Findings were correlated with collected clinical history. Results: Findings are summarized in the table. Unsupervised clustering and multi-parametric analysis showed a distinct methylation signature independent of age, sex, stage, site of metastasis, or type of treatment (adj. p<0.01). Pathway analysis identified c-AMP/MAPK and PI3K-Akt signaling pathways (adj. p=2.10E-05 and 8.19E-06, respectively) enrichment in non-responders. This coincided with significant increase of mutational events in c-AMP/MAPK and PI3K-Akt pathways (p= 0.0001) including deleterious events affectingPDE4DIP (p=0.0002), a negative regulator of mTORC1, in non-responders. C-AMP/MAPK/PI3K genomic alterations were associated with a worse OS and PFS but not worse response rate (p=0.04, p=0.01, and p=0.20). PDE4DIP deleterious events were associated with decreased response rate, worse OS and PFS (p=0.002; p=0.002;p=0.00003). Conclusions: Convergent epigenetic dysregulation of cAMP/MAPK signaling and inactivation of PDE4DIP is associated with worse outcome and lack of response to immunotherapy, respectively.