NAT10 as a central node in cancer biology: integrating epitranscriptomic regulation, metabolic reprogramming, and immune modulation.

N-acetyltransferase 10 (NAT10), the sole known mRNA N4-acetylcytidine (ac4C) writer, has emerged as a central regulator of cancer adaptation. Beyond its canonical role in RNA acetylation, NAT10 integrates environmental stress signals-including hypoxia, metabolic imbalance, and inflammatory cues-with epitranscriptomic remodeling to sustain malignant progression. Through selective ac4C deposition on mRNA and tRNA, NAT10 enhances transcript stability, amplifies translational output, and reinforces oncogenic signaling networks. These molecular effects converge on key adaptive programs, including glycolytic reprogramming, pentose phosphate pathway activation, amino acid biosynthesis, DNA damage repair, drug efflux, vascular remodeling, and immune suppression. Importantly, NAT10 operates within feedback circuits linking HIF-1α, Wnt/β-catenin, YAP1, and VEGFA(Vascular Endothelial Growth Factor A) signaling, thereby transforming transient stress responses into sustained adaptive states. This epitranscriptomic reinforcement underlies tumor plasticity and contributes to resistance against chemotherapy, targeted therapy, and immune checkpoint blockade. Emerging pharmacological strategies targeting NAT10, particularly in rational combination regimens, highlight its translational potential. However, key questions remain regarding ac4C reader proteins, substrate specificity, and context-dependent functions. In this review, we propose an integrated model in which NAT10 functions as a central adaptive node coupling RNA regulation, metabolic plasticity, and microenvironmental remodeling, and discuss future directions for exploiting this axis in precision oncology.