Targeting Nat10 reprograms regulatory T cells function to enhance anti-PD-1 immunotherapy sensitivity in lung cancer
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ABSTRACT: A significant challenge for improving the efficacy of immune checkpoint blockade (ICB) therapy is the concurrent activation of regulatory T (Treg) cells, which can dampen anti-tumor responses. 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. Combined administration of anti-PD-1 antibodies and a Nat10 inhibitor further impairs TI Treg-mediated immunosuppression, leading to enhanced tumor control. Our findings demonstrate that Nat10 is a key regulator of TI Treg cell fragility and function, and that its inhibition may enhance the therapeutic efficacy of ICB.
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE254341 | GEO | 2026/08/21
REPOSITORIES: GEO
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