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Targeted resistance to immune checkpoint therapy remains a clinical challenge, and a recent study reported by Xie et al provides novel insights into how RNA acetylation, particularly N4-acetylcytidine (ac4C), plays a pivotal role in shaping the tumor immune microenvironment in nasopharyngeal carcinoma (NPC). Through elucidation of the NAT10/DDX5/high mobility group box 1 axis, the authors demonstrate that enhanced ac4C modification suppresses CD4+ and CD8+ T-cell functionality, thereby facilitating tumor immune evasion and the resistance to anti-programmed cell death protein-1 therapy. This commentary evaluates the significance of these findings within the broader context of epitranscriptomic regulation research in oncology, identifies critical knowledge gaps regarding the equilibrium between immunosuppression and immune activation, and examines the therapeutic potential of NAT10 inhibition as a potential combinatorial approach in cancer immunotherapy. This work advances our understanding of how post-transcriptional RNA modifications influence tumor-immune interactions, establishing a conceptual framework for future investigations aimed at optimizing immunotherapeutic approaches in NPC and potentially other malignancies.