BACKGROUND: Immunosuppression significantly contributes to treatment failure in nasopharyngeal carcinoma (NPC). Messenger RNA (mRNA) modifications such as methylation and acetylation play crucial roles in immunosuppression. However, N4-acetylcytidine (ac4C), the only acetylation modification event has rarely been studied in NPC. METHODS: First, clinical tissue samples and nude mouse models were used to explore the expression of N-acetyltransferase 10 (NAT10) in NPC and its influence on it. Second, The Cancer Genome Atlas immune database and transgenic mouse peripheral blood immune cell panel were used to verify the immune cells mainly affected by NAT10. Then, NAT10 ac4C acetylation modification and expression of significantly upregulated transcription factors were explored by acetylated RNA immunoprecipitation sequence binding to RNA sequencing. Then, the downstream regulatory genes of CCAAT enhancer binding protein γ (CEBPG), dead box helicase 5 (DDX5) and helicase-like transcription factors (HLTF) were analyzed by luciferase report and chromatin Immunoprecipitation. Finally, the effect of inhibition of NAT10 on anti-programmed cell death protein 1 (PD-1) treatment sensitivity was verified by animal models. RESULTS: In this study, we aimed to explore the role of NAT10, the enzyme responsible for ac4C modification, in NPC progression and patient prognosis. Elevated NAT10 promoted NPC progression and correlated with poor prognosis in patients with NPC. NAT10-mediated ac4C modification of CONCLUSIONS: Our study elucidates the mechanism by which the