NAT10/ac4C/FOXP1 Promotes Malignant Progression and Facilitates Immunosuppression by Reprogramming Glycolytic Metabolism in Cervical Cancer

Immunotherapy has recently emerged as the predominant therapeutic approach for cervical cancer (CCa), driven by the groundbreaking clinical achievements of immune checkpoint inhibitors (ICIs), such as anti-PD-1/PD-L1 antibodies. N4-acetylcytidine (ac4C) modification, catalyzed by NAT10, is an important posttranscriptional modification of mRNA in cancers. However, its impact on immunological dysregulation and the tumor immunotherapy response in CCa remains enigmatic. Here, a significant increase in NAT10 expression in CCa tissues is initially observed that is clinically associated with poor prognosis. Subsequently, it is found that HOXC8 activated NAT10 by binding to its promoter, thereby stimulating ac4C modification of FOXP1 mRNA and enhancing its translation efficiency, eventually leading to induction of GLUT4 and KHK expression. Moreover, NAT10/ac4C/FOXP1 axis activity resulted in increased glycolysis and a continuous increase in lactic acid secretion by CCa cells. The lactic acid-enriched tumor microenvironment (TME) further contributed to amplifying the immunosuppressive properties of tumor-infiltrating regulatory T cells (Tregs). Impressively, NAT10 knockdown enhanced the efficacy of PD-L1 blockade-mediated tumor regression in vivo. Taken together, the findings revealed the oncogenic role of NAT10 in initiating crosstalk between cancer cell glycolysis and immunosuppression, which can be a target for synergistic PD-1/PD-L1 blockade immunotherapy in CCa. This study illustrates the oncogenic role of NAT10 in cervical cancer (CCa) and elucidates the mechanism by that the NAT10/ac4C/FOXP1 axis functions to accelerate glycolysis and promote infiltration of immunosuppressive Tregs into TME. Additionally, NAT10 knockdown contributes to enhancing PD-L1 blockade efficacy as a combinatorial therapy for CCa, highlighting the potential of targeting NAT10-mediated ac4C modification as a therapeutic strategy.image