EP300 and FCGR2B Emerge as Coordinated Mediators of Chromatin-Driven Immune Evasion in Melanoma Resistance

Immune checkpoint inhibitors targeting PD-1 have significantly improved outcomes in metastatic melanoma, yet 40–60% of patients exhibit primary resistance. While tumor-intrinsic epigenetic dysregulation has been implicated, its interplay with immune evasion remains poorly defined. In this study, we analyzed RNA-seq data from the GSE168204 dataset (n = 25 pre/on-treatment biopsies) comparing responders (n = 9) and non-responders (n = 16) to anti-PD-1 therapy. Using DESeq2 (|log2FC| > 1.5, padj < 0.05), we identified key differentially expressed genes (DEGs) in non-responders, including chromatin remodelers SMARCA2 (log2FC = 1.63, padj = 0.005) and KAT6B (log2FC = 2.8, padj = 1.2e-08), and the inhibitory receptor FCGR2B (log2FC = 2.196, padj = 0.001). Functional enrichment and protein–protein interaction analysis highlighted EP300 and KMT2A as hub genes linking histone acetylation (GO:0000123) to extracellular matrix remodeling (KEGG:04512). Transcription factor analysis identified STAT3 and RELA as central regulators of this resistance signature. These findings suggest that non-responder melanomas coordinately upregulate chromatin modifiers and immune checkpoints, promoting immune evasion. Our results nominate EP300 and FCGR2B as potential therapeutic targets to overcome resistance, warranting preclinical validation.