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

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.