BackgroundCutaneous 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.MethodsDNA 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.ResultsTwo 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.
Frontiers in Immunology published a clinical update in Infectious Disease on 24 Jun 2026.
The item focuses on The CpG island methylator phenotype defines an immune-cold and therapy-resistant subtype of cutaneous melanoma.
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