A tryptophan metabolism-related gene signature predicts prognosis and immune features in cutaneous melanoma.

Tryptophan metabolism is known to affect tumor immunity. However, the value of tryptophan metabolism-related genes (TMRGs) in predicting prognosis and reflecting immune status in skin cutaneous melanoma (SKCM) is not yet clear. We analyzed transcriptomic and clinical data of 457 patients with SKCM to elucidate the expression patterns of TMRGs and their links with survival and the tumor immune microenvironment. Unsupervised clustering and Cox regression were used to identify prognostic genes and build a TMRG-based risk model, which was then tested in independent cohorts. Immune features were further studied using bulk RNA sequencing and single-cell RNA sequencing data. In addition, functional experiments were performed in melanoma cell lines after IDO1 knockdown. The expression of TMRGs was widely altered in SKCM and was related to immune cell infiltration, tumor stemness, mutation features, and metabolic pathway activity. A five-gene risk model, comprising HADHA, GOT2, STAT1, CAT, and IDO1, divided patients into high- and low-risk groups with significantly different overall survival rates, and this model remained an independent predictor even after adjustment for clinicopathological factors. The two risk groups also showed apparent differences in the immune microenvironment, including immune cell composition and immune-related gene expression. Drug sensitivity analysis suggested that the two groups may respond differently to several chemotherapeutic and targeted drugs. In vitro experiments showed that IDO1 knockdown altered proliferation, migration, apoptosis, mitochondrial function, and tryptophan metabolism in melanoma cells. These findings suggest that tryptophan metabolism is closely linked to immune heterogeneity and clinical outcomes in patients with SKCM. Moreover, the TMRG-based risk model developed in this study provides complementary prognostic information and a basis for further investigation of metabolism-associated immune regulation in melanoma.