Dissecting the interplay between dedicator of cytokinesis 2 and neutrophil extracellular traps in sculpting the immune landscape and clinical outcome of melanoma using a single-cell atlas

Melanoma is an aggressive skin cancer with a rising incidence, posing clinical challenges because of limited prognostic tools and therapeutic resistance. Over recent years, neutrophil extracellular traps (NETs) have gained increasing attention in cancer biology for their role in tumor progression and immune modulation across various malignancies. The role of NETs in the progression of melanoma remains unclear. This study aimed to construct a NET-related prognostic model and elucidate the functional role of the key gene dedicator of cytokinesis 2 ( DOCK2 ) in the pathogenesis of melanoma. We integrated bulk RNA sequencing data from The Cancer Genome Atlas, the Genotype-Tissue Expression project, and the Gene Expression Omnibus, along with single-cell RNA sequencing data. A set of NET-related differentially expressed genes (NETRDEGs) was identified and proven to be enriched in immune-related pathways. A prognostic risk model based on NETRDEGs accurately predicted 1-, 3-, and 5-year survival (area under the curve > 0.7), with high-risk patients having worse outcomes. DOCK2 was identified as an overexpressed biomarker associated with a favorable prognosis and drug sensitivity. Low DOCK2 expression correlated with a higher tumor mutation burden and increased drug resistance. At the single-cell level, NETRG-associated transcriptional enrichment was prominent in macrophages; we characterized this heterogeneity and identified five novel subclusters. Analysis revealed a critical link between NETs and melanoma, identified a 235-gene NET signature, and established DOCK2 as a prognostic marker associated with the immune microenvironment. Furthermore, the expression of DOCK2 was correlated with the immune microenvironment and drug sensitivity, suggesting that targeting NET pathways could provide novel treatment strategies for melanoma.