Targeting Nat10 reprograms regulatory T cells function to enhance anti-PD-1 immunotherapy sensitivity in lung cancer

Thus, elucidating the mechanisms that maintain Treg suppressive function within the tumor microenvironment (TME) is critical. Here, we identify an accumulation of N-acetyltransferase 10 (Nat10)-modified RNA, particularly in Nat10⁺ Foxp3⁺ Treg cells, in human non-small cell lung cancer (NSCLC).

Genetic ablation of Nat10 in tumor-infiltrating (TI) Treg cells, or pharmacological inhibition of Nat10 expression, significantly reduces the PD-1⁺ Treg/CD8⁺ T cell ratio. These effects are accompanied by an increase in IFNγ⁺ Treg cells, a reduction in the immunosuppressive activity of Treg cells, and inhibition of tumor progression. Mechanistically, Nat10 promotes TI Treg cell infiltration and activation independently of its RNA-modifying function by directly interacting with Foxp3 and chromatin, shaping 3D genome architecture.