NAT10-Mediated ac4C Modification of circANKRD12 Reprograms the Tumor Microenvironment

Developing anticancer strategies that simultaneously target both tumor proliferation and the immunosuppressive microenvironment remains a major challenge. However, the role of chemical modifications in circular RNAs (circRNAs) in this process remains poorly understood. In this study, we identified circANKRD12 as a key substrate for N⁴-acetylcytidine (ac4C) modification, catalyzed by N-acetyltransferase 10 (NAT10) in multiple myeloma (MM). This ac4C modification promotes the translation of circANKRD12 into a novel 354-amino acid protein (circANKRD12_354aa). Functionally, circANKRD12_354aa interacts with histone deacetylase 2 (HDAC2) to stabilize the oncoprotein c-Myc, thereby driving MM cell proliferation. Moreover, circANKRD12 could be transferred from MM cells to natural killer (NK) cells, where it similarly suppressed NK cell cytotoxicity via the HDAC2/c-Myc axis, facilitating immune evasion. Clinically, circANKRD12 was upregulated in MM patients and correlated with poorer prognosis. Through high-throughput screening, we further identified the clinical antihistamine desloratadine as a direct binder of circANKRD12_354aa. Targeting the circANKRD12/HDAC2/c-Myc axis with desloratadine effectively suppresses MM growth and restores NK cell-mediated antitumor immunity in vivo. Our study reveals that NAT10-mediated ac4C modification of circANKRD12 plays a central role in coordinating tumor proliferation and immune dysfunction, establishing circANKRD12_354aa as a promising therapeutic target for restoring antitumor immunity in MM.