This study aimed to explore the prognostic value of necroptosis-related genes (NPRGs) in melanoma. A prognostic signature based on six NPRGs was constructed using the least absolute shrinkage and selection operator (LASSO) regression in the training cohort from The Cancer Genome Atlas (TCGA), with validation using the Gene Expression Omnibus (GEO) database (GSE65904). Patients were divided into high-risk and low-risk groups, and overall survival (OS) was compared using the Kaplan-Meier method. Cox regression analysis assessed the impact of clinicopathological features and risk scores on survival outcomes. The immune microenvironment was evaluated using the CIBERSORT method, and the relationship between clinical features, checkpoint gene expression, and risk scores was examined by correlation analysis. Gene expression of the six NPRGs was validated using the GEPIA2 database and immunohistochemistry (IHC). The prognostic signature predicted worse OS in the high-risk group, and this was confirmed in the validation cohort. Risk scores were found to independently predict survival in melanoma patients. Significant differences in the immune microenvironment and checkpoint gene expression were observed between risk groups. The necroptosis score showed a positive correlation with natural killer cells and M2 macrophages, and a negative correlation with T-cell and B-cell infiltration. Lower levels of immune checkpoint gene expression were observed in the high-risk group. IHC results confirmed the gene expression trends of NPRGs from the GEPIA2 database. In conclusion, the prognostic signature based on NPRGs can serve as a novel prognostic predictor in melanoma patients and reflect the immune microenvironment.

Yanqing Wang, Xianghui Meng, Ke Yang, Juhua Zhao. Construction and Validation of a Necroptosis-Related Gene Signature Associated with the Tumor Microenvironment in Melanoma. Frontiers in Medical Science Research (2025), Vol. 7, Issue 5: 29-42. https://doi.org/10.25236/FMSR.2025.070505.

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