Regulatory T cells subgroups in the tumor microenvironment cannot be overlooked: Their involvement in prognosis and treatment strategy in melanoma

Abstract Background Melanoma, the most lethal form of skin cancer, presents substantial challenges despite effective surgical interventions for in situ lesions. Regulatory T cells (Tregs) wield a pivotal immunomodulatory influence within the tumor microenvironment, yet their impact on melanoma prognosis and direct molecular interactions with melanoma cells remain elusive. This investigation employs single‐cell analysis to unveil the intricate nature of Tregs in human melanoma. Methods Single‐cell RNA and bulk sequencing data, alongside clinical information, were obtained from public repositories. Initially, GO and GSEA analyses were employed to delineate functional disparities among distinct cell subsets. Pseudotime and cell–cell interconnection analyses were conducted, followed by an endeavor to construct a prognostic model grounded in Treg‐associated risk scores. This model's efficacy was demonstrated via PCA and K‐M analyses, with multivariate Cox regression affirming its independent prognostic value in melanoma patients. Furthermore, immune infiltration analysis, immune checkpoint gene expression scrutiny, and drug sensitivity assessments were performed to ascertain the clinical relevance of this prognostic model. Results Following batch effect correction, 80 025 cells partitioned into 31 clusters, encompassing B cells, plasma cells, endothelial cells, fibroblasts, melanoma cells, monocytes, macrophages, and T_NK cells. Within these, 4240 CD4+ T cells were subclassified into seven distinct types. Functional analysis underscored the immunomodulatory function of Tregs within the melanoma tumor microenvironment, elucidating disparities among Treg subpopulations. Notably, the ITGB2 signaling pathway emerged as a plausible molecular nexus linking Tregs to melanoma cells. Our prognostic signature exhibited robust predictive capacities for melanoma prognosis and potential implications in evaluating immunotherapy response. Conclusion Tregs exert a critical role in immune suppression within the melanoma tumor microenvironment, revealing a potential molecular‐level association with melanoma cells. Our innovative Treg‐centered signature introduces a promising prognostic marker for melanoma, holding potential for future clinical prognostic assessments.