Integrating multi-omics data to resolve patterns of ion channel regulation in melanoma and predict tumor treatment response

Skin cutaneous melanoma (SKCM) represents a highly aggressive malignancy with rising incidence, characterized by early metastatic potential and development of treatment resistance in advanced stages. While ion channel-related genes (ICRGs) demonstrate therapeutic relevance across cancers, their role in SKCM remains incompletely defined. A comprehensive assessment of ICRG regulatory patterns was conducted in SKCM samples using single-cell spatial transcriptomic and multi-omics data. These patterns were correlated with tumor microenvironment (TME) cell infiltration characteristics to construct ICRG scores quantifying tumor-specific ICRG modification patterns. The ICRG.Gene.cluster stratifies samples into two distinct subpopulations representing divergent immune phenotypes. An ICRG scoring system is constructed based on ICRG phenotype genes and validated in independent cohorts. Through ICRG-associated gene profiling, CD8⁺ T cells are categorized into five subsets, all exhibiting significant temporal dynamics in pseudotime analysis. Spatial transcriptomics confirms prominent co-localization spots between the C3 CD8⁺ T cell subset and melanoma cells. SCENIC analysis identifies that specific ICRG genes function as target nodes regulated by transcription factors. Core ICRG genes demonstrate elevated expression in both cell lines and clinical specimens, supporting their potential role as disease-associated genetic risk loci. ICRG modification patterns provide critical insights into TME infiltration heterogeneity, enabling refined prognostic assessment and therapeutic targeting strategies.