ArticleFrontiers in immunology2026
The CpG island methylator phenotype defines an immune-cold and therapy-resistant subtype of cutaneous melanoma.
Article in Frontiers in immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Cutaneous melanoma (CM) displays marked clinical heterogeneity and variable responses to immune checkpoint blockade (ICB). The CpG Island Methylator Phenotype (CIMP), characterized by widespread promoter hypermethylation, has been implicated in tumor progression, but its role in shaping the tumor immune microenvironment and therapeutic response remains unclear. Methods: DNA methylation and transcriptomic data from The Cancer Genome Atlas (TCGA) were analyzed and validated in an external cohort (GSE120878). Unsupervised clustering identified CIMP subtypes. Integrative analyzes included promoter-focused methylation-expression coupling (ELMER), immune deconvolution (GSVA, MCPcounter, ESTIMATE), genomic profiling, and drug sensitivity prediction (GDSC). Clinical relevance was further assessed in an independent ICB-treated cohort (PRJEB23709). Functional assays evaluated the role of NRAS in melanoma cell lines. Results: Two epigenetic subtypes were defined: CIMP+ (24.9%) and CIMP- (75.1%). CIMP+ tumors were associated with older age and male sex and exhibited significantly worse overall and progression-free survival, remaining an independent prognostic factor after multivariable adjustment. Integrative analysis identified 2,510 hypermethylated promoter probes linked to reduced expression of 1,707 genes enriched in interferon-γ and inflammatory pathways, although these associations likely reflect both tumor-intrinsic regulation and differences in cellular composition. Consistently, CIMP+ melanomas displayed an immune-depleted bulk-tumor profile, with reduced immune checkpoint gene expression, lower immune/stromal scores, and decreased leukocyte-associated methylation signals. Genomically, CIMP+ tumors were enriched for NRAS and ARID2 mutations, showed fewer BRAF alterations, and exhibited significantly increased copy-number alterations and chromosomal instability. In an ICB-treated cohort, transcriptome-inferred CIMP+ status was significantly enriched in non-responders and associated with inferior survival. Drug sensitivity modeling identified multiple candidate compounds, including elesclomol and Wnt pathway inhibitors. Functionally, NRAS knockdown suppressed proliferation, migration, and invasion while promoting apoptosis and epithelial-mesenchymal transition reversal. Conclusion: CIMP defines a clinically relevant melanoma subtype characterized by epigenetic remodeling, genomic instability, and an immune-poor tumor microenvironment, and is associated with poor prognosis and reduced benefit from immunotherapy. These findings suggest that therapeutic resistance in CIMP+ melanoma is multifactorial and highlight potential avenues for targeted intervention.
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