Vasoactive intestinal peptide associated 8-gene signature with prognostic and immune associations in melanoma

Vasoactive intestinal peptide (VIP) plays a multifaceted role in cancer biology, yet its prognostic and immunological implications in melanoma remain underexplored. This study aimed to construct a VIP-related gene signature for risk stratification and to explore its potential associations with the tumor immune microenvironment and drug sensitivity in melanoma. RNA-sequencing data and clinical information were obtained from TCGA-SKCM (n = 477, training set) and GSE65904 (n = 209, validation set). A VIP-related prognostic signature (VIPsig) was developed using stepwise Cox regression and Gradient Boosting Machine algorithms. Patients were stratified into high- and low-risk groups based on the median risk score. Somatic mutations, immune infiltration, drug sensitivity, and functional enrichment were further analyzed. A nomogram integrating clinical factors was developed and validated. Single-cell RNA-seq data (GSE115978) were reanalyzed to characterize cellular expression patterns. A preliminary pan-cancer analysis indicated potential dysregulation of VIP pathway genes. In melanoma, we identified an 8-gene signature (CD28, CD80, CD86, CTLA4, FAS, IFNG, IL10, and IL12A) associated with survival. In the training set, high-risk patients exhibited significantly worse overall survival (OS) compared to low-risk patients (HR = 2.96, 95% CI: 2.24-3.92, P < .001). This was validated in the GSE65904 cohort (HR = 1.87, 95% CI: 1.26-2.77, P = .002). The VIPsig demonstrated discriminative ability with 1-, 3-, and 5-year AUCs of 0.760 (95% CI: 0.675-0.845, P < .001), 0.749 (95% CI: 0.692-0.807, P < .001), and 0.770 (95% CI: 0.717-0.823, P < .001) in the training set, respectively. Functionally, the signature was significantly associated with immune cell infiltration and immune checkpoint expression. In silico drug sensitivity analysis suggested potential associations with estimated IC50 values for several agents, though these findings require experimental validation. A nomogram integrating VIPsig with clinicopathological factors showed improved net benefit in decision curve analysis. The VIP-based signature demonstrates robust prognostic value for melanoma survival and reflects the tumor immune microenvironment status. Exploratory analyses suggest potential associations with in silico drug sensitivity estimates; however, its utility for treatment response prediction remains unvalidated and warrants further investigation in prospective melanoma cohorts treated with immune checkpoint inhibitors.