GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE254nnn/GSE254341/primaryOK200Methylation profiling Mus musculusHomo sapiensMethylation profiling by high throughput sequencing Genome binding/occupancy profiling by high throughput sequencing Expression profiling by high throughput sequencing Otherhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE254341GEOGSEfalseTargeting Nat10 reprograms regulatory T cells function to enhance anti-PD-1 immunotherapy sensitivity in lung cancerA 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.2026/08/21GSE254341GSM8038005GSM8038004GSM8038003GSM8038022GSM8038021GSM8038020GSM9092579GSM9092578GSM9092577GSM8038009GSM9092576GSM8038008GSM9092575GSM8038007GSM8038006GSM9092583GSM9092582GSM9092581GSM9092580GSM8038016GSM8038015GSM8038014GSM8038013GSM8038012GSM8038011GSM8038010GSM9872194GSM9872193GSM9872196GSM9872195GSM9872198GSM9092586GSM9872197GSM8038019GSM8038018GSM9092585GSM9092584GSM9872199GSM8038017GSM98721922467624247254341 Mus musculusHomo sapiens