N4-acetylcytidine modification bridges metabolic reprogramming and immune evasion in cancer: mechanisms and therapeutic implications.

N4-acetylcytidine (ac4C) is an evolutionarily conserved RNA modification catalyzed by N-acetyltransferase 10 (NAT10), representing the sole known acetylation modification in eukaryotic mRNA. Recent studies have revealed that ac4C modification plays multifaceted roles in cancer progression by regulating mRNA stability and translation efficiency. Notably, emerging evidence demonstrates that NAT10-mediated ac4C modification simultaneously orchestrates tumor metabolic reprogramming and immune evasion, two hallmarks of cancer that are increasingly recognized as interconnected processes. In metabolic regulation, ac4C modification enhances the stability and translation of key glycolytic enzymes, including hexokinase (HK1/2), enolase 1 (ENO1), lactate dehydrogenase A (LDHA), and phosphoglycerate mutase 1 (PGAM1), thereby promoting the Warburg effect. Concurrently, ac4C modification facilitates immune evasion through multiple mechanisms, including upregulation of PD-L1 expression, suppression of T cell function, and inhibition of type I interferon signaling. Importantly, glycolysis-driven lactate accumulation creates an immunosuppressive tumor microenvironment, suggesting that ac4C serves as a molecular bridge connecting metabolic reprogramming to immune escape. Targeting NAT10 with inhibitors such as Remodelin has shown promising preclinical efficacy, particularly when combined with immune checkpoint inhibitors. This review comprehensively summarizes the current understanding of ac4C modification in tumor metabolism and immunity, highlights the metabolic-immune crosstalk mediated by ac4C, and discusses the therapeutic potential of targeting this modification for cancer treatment. We also highlight emerging controversies regarding ac4C stoichiometry in human mRNA, cell-type-specific functions of ac4C in the tumor microenvironment, and the expanding regulatory network encompassing non-coding RNAs and crosstalk with other RNA modifications including m5C, pseudouridine, and m6Am.