Immune checkpoint inhibitors (ICIs), such as anti-PD-1 and anti-CTLA-4, have significantly advanced melanoma treatment by reactivating the immune system to target cancer cells. However, a substantial portion of patients do not respond or develop resistance, highlighting the need for more effective predictive biomarkers. Dysregulation of transcriptional programs has been implicated in cancer progression and immune evasion, with transcription factors (TFs) playing a crucial role. In this study, we investigated transcriptional gene signatures (TGSs) for their potential to predict ICI resistance in melanoma by analyzing two independent clinical trial datasets. Among the identified TFs, NFATC2 (Nuclear Factor of Activated T Cells 2) was observed to be a promising marker for resistance to anti-PD-1 therapy. NFATC2, a regulator of T cell activation, may be co-opted by melanoma cells to evade immune surveillance. Our analysis indicated that elevated NFATC2 TGS scores were associated with ICI resistance and poorer survival outcomes across multiple melanoma cohorts. Validation in independent datasets further suggested NFATC2's potential predictive value, particularly in patients without liver metastasis or with prior anti-CTLA-4 therapy. Elevated NFATC2 TGS scores also correlated with reduced immune cell infiltration, specifically of CD8+ T cells, increased markers of T cell exhaustion, and higher tumor purity. These findings support NFATC2 TGS as a candidate biomarker for stratifying melanoma patients and potentially informing ICI therapy response. Further research into NFATC2-associated immune evasion mechanisms may offer insights for overcoming resistance to immunotherapy.