44 metastatic melanoma patients in both the high- and low-risk groups did not exhibit significant clinical benefits from ICI therapy (Wilcox test, P=0.69) (Figure S14); however, we separately explored the effect of the methylation level of these three genes (POU3F3, SYN2, and TMEM178A) on immunotherapy, finding that patients with low SYN2 methylation levels showed a poorer clinical response to ICI therapy than those with high methylation levels (Wilcox test, P=0.024) (Figure 5G). Here, SYN2 is linked to metastatic melanoma.