Targeting the NAT10-HDAC4 positive feedback loop counteracts immunosuppression in breast cancer

BACKGROUND: N-acetyltransferase 10 (NAT10) mediated N4-acetylcytidine (ac4C) modification has been implicated in tumor progression; however, the precise role and underlying mechanism of NAT10 in breast cancer progression remain largely undefined. METHODS: The expression and prognostic significance of NAT10 in breast cancer were evaluated using clinical tissue samples and public databases. Functional assays were performed in vitro and in vivo to assess the effects of NAT10 on tumor growth and immune evasion. Mechanistic studies, including RNA immunoprecipitation (RIP), ac4C RNA immunoprecipitation (acRIP), and co-immunoprecipitation (Co-IP), were conducted to elucidate the interaction between NAT10 and histone deacetylase 4 (HDAC4) and their roles in regulating NF-κB signaling and programmed death-ligand 1 (PD-L1) expression. RESULTS: NAT10 expression was significantly upregulated in breast cancer and correlated with poor patient prognosis. NAT10 mediated ac4C modification enhanced the stability of HDAC4 mRNA, thereby promoting HDAC4 expression. Conversely, HDAC4 stabilized NAT10 protein through post-transcriptional deacetylation, forming a self-reinforcing regulatory loop. Elevated HDAC4 activated the NF-κB signaling pathway, resulting in increased PD-L1 transcription and enhanced immune evasion of breast cancer cells. Inhibition of the NAT10/HDAC4/NF-κB axis markedly reduced PD-L1 expression and restored antitumor immune responses. CONCLUSION: Our findings identify a self-reinforcing NAT10/HDAC4 signaling circuit that drives breast cancer progression and immune evasion. Targeting NAT10 represents a promising therapeutic strategy to overcome immunosuppression and improve patient outcomes in breast cancer.