Targeting N-acetyltransferase 10 reprograms Treg function to enhance anti–PD-1 immunotherapy sensitivity in murine lung tumors

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Abstract

A significant challenge for improving the efficacy of immune checkpoint blockade (ICB) therapy is the concurrent activation of Tregs, which can dampen antitumor responses. Thus, elucidating the mechanisms that maintain Treg-suppressive function within the tumor microenvironment is critical. Here, we identified an accumulation of N-acetyltransferase 10–modified (NAT10-modified) RNA, particularly in NAT10+FOXP3+ Tregs, in human non–small cell lung cancer. Genetic ablation of Nat10 in tumor-infiltrating (TI) Tregs, or pharmacological inhibition of NAT10 expression, significantly reduced the PD-1+ Treg/CD8+ T cell ratio. These effects were accompanied by an increase in IFN-γ+ Tregs, a reduction in the immunosuppressive activity of Tregs, and inhibition of tumor progression. Mechanistically, NAT10 promotes TI Treg infiltration and activation independently of its RNA-modifying function by directly interacting with FOXP3 and chromatin, modulating local 3D chromatin contacts. Combined administration of anti–PD-1 antibodies and a NAT10 inhibitor further impaired TI Treg–mediated immunosuppression, leading to enhanced tumor control. Our findings demonstrate that NAT10 is a key regulator of TI Treg fragility and function and that its inhibition may enhance the therapeutic efficacy of ICB.

Authors

Xuewei Qi, Dan Cui, Xiao Li, Wenfan Fu, Handong Ma, Wenting Guo, Jiabao Wang, Jiaxi Song, Jiaxin Ma, Jing Yang, Haoyu Yu, Yuting Hong, Qian Wang, Susu Luo, Jia Wang, Baixing Wu, Shanshan Li, Hao Cheng, Min Cheng, Bin Li, Kaiming Zhang, Jia Li, Fengyin Li