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The TCGA melanoma datasets were used for validation. Pre-therapy lesions (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200928) from a cohort of MM patients treated with adjuvant immune checkpoint blockade were characterized for the DNA methylation profile. Impact of a DNMT inhibitor on DNA methylation and transcriptomic profiles of melanoma cell lines was investigated by EPIC arrays and Clariom S arrays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Four tumor subsets (i.e. DEMethylated, LOW, INTermediate and CIMP) with progressively increasing levels of DNA methylation were identified in EPICA, TCGA MM and TCGA primary melanoma cohorts. EPICA patients with LOW methylation tumors exhibited a significantly longer survival and a lower progression rate to more advanced AJCC stages, compared to patients with CIMP tumors. In an adjuvant immune checkpoint blockade cohort, patients with DEM\/LOW pre-therapy lesions showed significantly longer relapse-free survival compared to those with INT\/CIMP lesions. RNA-seq data analysis revealed that LOW and CIMP EPICA tumors showed opposite activation of master molecules influencing prognostic target genes, and differential expression of immunotherapy response and melanoma differentiation signatures. Compared to CIMP tumors, LOW lesions showed enrichment for CD8\n                      <jats:sup>+<\/jats:sup>\n                      TCF-1\n                      <jats:sup>+<\/jats:sup>\n                      PD-1\n                      <jats:sup>+<\/jats:sup>\n                      TIM-3\n                      <jats:sup>\u2212<\/jats:sup>\n                      pre-exhausted and CD8\n                      <jats:sup>+<\/jats:sup>\n                      TCF-1\n                      <jats:sup>\u2212<\/jats:sup>\n                      PD-1\n                      <jats:sup>+<\/jats:sup>\n                      TIM-3\n                      <jats:sup>+<\/jats:sup>\n                      exhausted T cells, more frequent retention of HLA Class I antigens and a de-differentiated melanoma phenotype. The differentiation and immune-related transcriptional features associated with LOW vs CIMP lesions were tumor-intrinsic programs retained in-vitro by melanoma cell lines. Consistently, treatment of differentiated melanoma cell lines with a DNMT inhibitor induced global DNA de-methylation, promoted de-differentiation and upregulated viral mimicry and IFNG predictive signatures of immunotherapy response.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These results reveal the biological, prognostic and therapeutic relevance of DNA methylation classes in MM and support methylome targeting strategies for precision immunotherapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-025-03474-9","type":"journal-article","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T07:38:52Z","timestamp":1752824332000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Integrated multi-omics profiling reveals the role of the DNA methylation landscape in shaping biological heterogeneity and clinical behaviour of metastatic melanoma"],"prefix":"10.1186","volume":"44","author":[{"given":"Andrea","family":"Anichini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca P.","family":"Caruso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Lagano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa M. 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Patients in the adjuvant ICB cohort were treated at the Center for Immuno-Oncology, Department of Oncology, University Hospital of Siena, Siena, according to daily practice or within clinical trials (CA-209\u2013238 (NCT02388906); CA-209\u2013915 (NCT03068455). All patients provided an informed consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"A.M.D.G. Advisor\/board member for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; Bristol Myers Squibb; IncytePierre Fabre; Sanofi; GlaxoSmithKline; Novartis; SunPharma; Immunocore. Honoraria for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; Roche; Bristol Myers Squibb; Sanofi; Pierre Fabre; GlaxoSmithKline; Vyvamed. M.M. Advisor\/board member for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; Roche; Bristol Myers Squibb; Incyte; AstraZeneca; Amgen; Pierre Fabre; Eli Lilly; Sanofi; GlaxoSmithKline; Alfasigma; Merck Serono; and owns shares in Epigen Therapeutics srl; honoraria for Merck. M.C. Fundings: Moderna Therapeutics. A.C. and S.C. own shares in Epigen Therapeutics srl.  Other authors have nothing to declare.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"212"}}