Mapping the role of cytokine signaling at single-cell and structural resolution in uveal melanoma.

To better understand the complexity of the tumor microenvironment and to identify novel treatment strategies for uveal melanoma (UVM), we analyzed single-cell RNA sequencing (scRNA-seq) data from eight primary UVM eye tissues and three metastatic UVMs in the liver (GSE139829). We integrated this with bulk RNA-seq data from UVM patients derived from TCGA-UVM and GSE84976 cohorts. Our study focused on cytokine signaling in immune-related genes (CSIRGs), revealing distinct cellular compositions, intercellular interactions, and prognostic implications in UVM. We identified 137 cytokine signaling-related genes in UVM, with ISG20 significantly upregulated and linked to advanced stages and poor prognosis. Recognized for immune regulation, ISG20 emerged as a key survival predictor and therapeutic target from a risk model using Cox regression and LASSO, effectively categorizing patients by survival risk. Furthermore, differential drug response analysis revealed distinct sensitivities to drugs between the risk groups. Immune infiltration analysis showed a diverse immune landscape, potentially influencing response to immunotherapy. Structural prediction using AlphaFold 2 technology and molecular docking analyses revealed interactions between ISG20 and the therapeutic candidate decitabine. This study combines scRNA-seq analysis with structural biology approaches to unravel the molecular complexity of UVM, emphasizing the prognostic and therapeutic relevance of CSIRGs, particularly ISG20.