Characterization of T‐Cell Ubiquitination in Melanoma and Development of a Risk Signature Using Single‐Cell and Bulk RNA ‐Seq

ABSTRACT Cutaneous melanoma (CM) is an aggressive cancer where early intervention is crucial, but the prognostic role and mechanisms of ubiquitination‐related genes (URGs) in immune regulation remain unclear. This study aimed to develop a URG‐based prognostic signature and explore its relationship with immune modulation in CM. We integrated single‐cell RNA sequencing (scRNA‐seq) and bulk RNA‐seq data, identifying prognostic URGs through univariate and multivariate Cox regression. A six‐gene signature (UBE2L6, SPSB1, PSMB9, PSMB10, RNF213 and ATXN3) was established and validated. The signature effectively stratified patients into high‐ and low‐risk groups, with significant survival differences. Pathway analysis revealed immune‐related processes, such as ‘cytokine‐cytokine receptor interaction’ and ‘antigen processing and presentation’, enriched in the low‐risk group. Immune cell infiltration analysis demonstrated significant differences in the abundance of 12 immune cell types between risk groups. Notably, PSMB9 expression was positively correlated with CD8 + T cell abundance ( r = 0.64, p < 0.05). scRNA‐seq analysis highlighted T cells as a key cell type, with all six prognostic genes showing dynamic expression changes during T cell differentiation. Our findings suggest that URGs influence CM prognosis by modulating the immune microenvironment, offering new insights for immunotherapeutic strategies.