NAT10‐Mediated ac4C Modification of circANKRD12 Reprograms the Tumor Microenvironment

ABSTRACT 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 N ⁴ ‐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.