ArticleBiology direct2026
Single-cell multi-omics dissection of RevitalAge Markers uncovers age-dependent immunotherapy resistance and druggable targets in melanoma.
Article in Biology direct, 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
Aging-related molecular reprogramming profoundly influences melanoma progression and therapeutic sensitivity, yet underlying mechanisms remain poorly understood. We constructed a comprehensive multi-omics atlas integrating mutations, transcription, methylation, and copy number variations, utilizing the MOFA algorithm to uncover key age-driving factors. Among 20 factors, Factor6 exhibited significant negative age correlation and survival protection (HR = 0.95, P = 4.494e-05), defined as "RevitalAge Marker (RAM)". Integration of three single-cell RNA sequencing datasets revealed 4,796 RAM+ cells (predominantly endothelial cells and fibroblasts) exerting tumor-suppressive functions through VEGFA-VEGFR2 angiogenic pathways and mitochondrial ATP synthesis, while 7,229 RAM- cells (dominated by malignant cells) exhibited enhanced EMT, hypoxic adaptation, and MAPK signaling activation. RAM+ cells were governed by ZFP42 and IRF8 maintaining anti-tumor immunity, while RAM- cells controlled by ILF2 and ISL1 promoted metastasis and immune evasion, with RAM- malignant cells enriched in patients over 65 years and associated with immunotherapy resistance. Machine learning analysis of RAM-associated genes identified five core signatures (GPR143, ST3GAL4, RAB38, GMPR, FDFT1) demonstrating superior immunotherapy response prediction (AUC = 0.78-1.00). Drug sensitivity profiling revealed ST3GAL4 exhibited strong correlations with AZ628 (pan-RAF inhibitor) and RDEA119 (MEK inhibitor), which was further validated by molecular docking showing excellent binding affinities (binding energies: -8.7 and - 7.2 kcal/mol). This study provides structural evidence for targeted therapeutic strategies in ST3GAL4-overexpressing melanoma and establishes foundations for age-stratified immunotherapy.
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