Background <p>Cutaneous melanoma (SKCM) is an aggressive malignancy with poor prognosis. Recent studies have shown that immune cells in the tumor microenvironment, particularly resting regulatory T cells (Resting Treg), play a crucial role in tumor development and immune evasion. However, the exact relationship between these immune cells and SKCM, as well as the underlying mechanisms, remain incompletely understood.</p> Methods <p>In this study, we analyzed immune cell subpopulations in SKCM using single-cell RNA sequencing (scRNA-seq) data and employed Mendelian randomization (MR) to assess the impact of genetic variations on the proportion of Resting Treg cells. Additionally, we constructed a prognostic model based on Resting Treg-related genes and performed independent prognostic analyses to evaluate the accuracy of this model in predicting the survival of SKCM patients.</p> Results <p>Through scRNA-seq data analysis, we identified various T cell subtypes associated with SKCM and found extensive interactions between Resting Treg cells and other T cell subpopulations. The MR analysis showed that the association between specific SNPs and the proportion of CD39 + Resting Treg cells remained significant even after accounting for pleiotropic bias. The constructed prognostic model demonstrated reliable predictive ability in predicting the survival of SKCM patients, with acceptable predictive ability as indicated by ROC curve analysis.</p> Conclusion <p>This study elucidates the potential role of Resting Treg cells in the development of SKCM and constructs an effective prognostic model. These findings not only enhance our understanding of the tumor immune microenvironment but also provide a new perspective for personalized treatment of SKCM. Future research is needed to further validate these results and explore the specific functions of Resting Treg cells in the tumor microenvironment.</p>