Decitabine reverses innate immune gene suppression in rare melanomas

Rare melanoma subtypes, including acral, mucosal, and uveal melanomas, exhibit limited responses to immune checkpoint inhibitors (ICIs), yet the molecular mechanisms of immune resistance remain poorly defined. This study aimed to characterize transcriptional programs associated with immune evasion across melanoma subtypes and identify strategies to restore immune gene expression in rare melanomas. We performed transcriptomic profiling of melanoma patient-derived xenografts (PDXs) and publicly available tumor datasets to compare intratumoral gene expression across cutaneous and rare melanoma subtypes. Cross-subtype analysis revealed convergent downregulation of innate immune pathogen sensing (IIPS) and type I interferon signaling pathways in rare melanomas compared to cutaneous tumors. Lower IIPS expression correlated with non-response to PD-1 blockade, associated with reduced CD8⁺ and memory CD4⁺ T cell infiltration and enrichment of M2 macrophages inferred by CIBERSORT. Immunomodulatory compounds were screened in vitro to identify IIPS inducing drugs, and decitabine was further evaluated in mucosal and uveal melanoma xenograft models. Decitabine treatment robustly induced IIPS and antigen presentation genes in rare melanoma cell lines and xenografts, with RNA-seq confirming IIPS re-expression as the dominant transcriptional consequence. Silencing of IIPS genes represents a recurrent immune evasion mechanism in rare melanomas. Decitabine reverses this silencing, restoring innate and adaptive immune gene expression, and may serve as a therapeutic priming strategy to enhance ICI responsiveness in patients with rare melanoma subtypes.