NAT10 and ac4C modification in cancer immunity and metabolism: emerging mechanisms and therapeutic potential

Tumor immunity and metabolism are interconnected through the tumor microenvironment (TME), with RNA modifications playing pivotal epigenetic regulatory roles. N4- acetylcytidine (ac4C) is the first acetylated modification identified on eukaryotic RNAs, and N- acetyltransferase 10 (NAT10) is the key enzyme catalyzing this modification, depositing ac4C on transfer RNA(tRNA), ribosomal RNA(rRNA), messenger RNA(mRNA), and long non-coding RNA(lncRNA) via its specific localization and expression. However, its systematic functions in tumor immunity and metabolic reprogramming have not been comprehensively summarized for clinical translation.

This review systematically synthesizes recent research on NAT10-mediated ac4C modification in oncology, covering data from cell experiments, animal models, and clinical sample analyses across multiple tumor types (e.g. breast cancer(BC), liver, cervical cancer(CC). It integrates findings on NAT10's dual enzymatic activities, subcellular localization, regulation of cell cycle and DNA damage repair, mechanisms in TME remodeling and metabolic reprogramming, as well as preclinical progress of NAT10 inhibitors.

NAT10 possesses dual enzymatic activities of protein acetylation and RNA acetylation. Its subcellular localization is redistributed in tumor tissues, which is closely associated with tumorigenesis and progression. In TME remodeling, the NAT10-ac4C axis regulates inflammasome activation, suppresses T-cell function, promotes M2 macrophage polarization, andrecruits tumor- associated macrophages, thereby creating an immunosuppressive microenvironment.In metabolic reprogramming, this axis drives glycolysis by stabilizing hexokinase 2(HK2)/lactate dehydrogenase A (LDHA) mRNA, regulates amino acid metabolism through the Khib-ac4C cascade, and modulates fatty acid metabolism and ferroptosis resistance. Furthermore, high NAT10 expression is associated with chemotherapy and radiotherapy resistance in various tumors, and its inhibitor Remodelin has shown synergistic antitumor effects when combined with immune checkpoint inhibitors in preclinical studies.

NAT10-mediated ac4C modification is a critical regulatory node integrating tumor immunity and metabolism, serving as a promising potential target for precision cancer therapy. Current research still faces challenges such as insufficient sensitivity and specificity of ac4C detection technologies, unclearcell-type-specific mechanisms of NAT10, limited delivery efficiency of inhibitors, and the existence of compensatory pathways. Future research should focus on optimizing ac4C detection technologies, clarifying cell-type-specific mechanisms, developing targeted delivery systems, and further exploring the clinical translational value of combining NAT10-targeted therapy with immune checkpoint blockade, so as to provide new strategies and technical support for cancer treatment.