Background: Melanoma is highly immunogenic and therefore suitable for 
immunotherapy, but the efficacy is limited by response rate. In several types of 
tumor, tumor mutation burden (TMB) and immune infiltration have been reported to 
predict the response to immunotherapy, although each has its limitations. In the 
current study, we aimed to explore the association of TMB with immune 
infiltration and prognosis in cutaneous melanoma. Methods: The data of cutaneous 
melanoma used for analyses was downloaded from The Cancer Genome Atlas (TCGA) 
database. The mutation data was sorted using "maftools" R package. TMB was 
estimated and then patients were divided into two groups based on TMB. The 
association of TMB with prognosis and clinical characteristics was explored. 
Differential analysis between two TMB groups was performed using "DESeq2" R 
package to identify differentially expressed genes (DEGs). The function 
enrichment analyses of DEGs were conducted to screen critical pathways. Besides, 
DEGs were further filtered to identify two hub genes, based on which a risk 
score model and nomogram for predicting prognosis were conducted, and the 
validation was performed using three datasets from Gene Expression Omnibus (GEO) 
database. Finally, CIBERSORT algorithm and TIMER database were used to assess 
the effect of TMB and hub genes on immune infiltration. Results: The most common 
mutation was C > T, and the top three frequently mutated genes were TTN, MUC16, 
and BRAF. Higher TMB indicated better survival outcomes and lower pathological 
stages. 735 DEGs were identified and mainly involved in immune-related and 
adhesion-related pathways. The risk score model and nomogram were validated 
using receiver operating characteristic (ROC) curves and calibration curves, and 
exhibited relatively high predictive capability. Decision curve analysis (DCA) 
was used to assess clinical benefit. As for immune infiltration, the proportion 
was higher for macrophages M1 and M2 in the high-TMB group, while lower for 
memory B cells and regulatory T cells. Conclusions: In cutaneous melanoma, TMB 
was positively correlated with prognosis. The risk score model and nomogram can 
be conveniently used to predict prognosis. The association of TMB with immune 
infiltration can help improve the predicting methods for the response to 
immunotherapy.