2026-10-14T21:55:58Z https://www.scidb.cn/oai

10.57760/sciencedb.23744 2025-04-21T16:20:49Z

2025-04-21 DNMT1 inhibition reprograms T cells to NK-like cells with potent antitumor effects doi:10.57760/sciencedb.23744 en BCL11B ablation reprograms T cells into induced-T-to-NK cells (ITNKs). However, it remains unclear how BCL11B suppresses NK cell programs in T cells. Here, we demonstrate that the maintenance DNA methyltransferase DNMT1 interacts with BCL11B and safeguards the transition from T to NK-like cells. This involves a collective cooperation between DNMT1 and BCL11B that increases BCL11B protein stability and the fidelity of DNA methylation maintenance for NK cell-related genes, while also jointly suppressing NK cell programs in T cells. Moreover, DNMT1 maintains the epigenetic silencing of a distinct subset of NK cell-related genes independent of BCL11B. DNMT1 inhibitor (DNMT1i) or DNMT1 depletion reprograms T cells and chimeric antigen receptor (CAR) T cells into NK-like cells. These NK-like cells exhibit more robust antitumor effects than BCL11B-deficient ITNKs and parental CAR-T cells. Moreover, H3K27me3 synergizes with DNA methylation to repress NK cell-related pathways, and the combination of an EZH2 inhibitor (EZH2i) and DNMT1i potentiate both the reprogramming and cytotoxicity of NK-like cells. Our findings uncover the molecular mechanisms that safeguard T cell identity and provide a rationale for deriving NK-like cell sources with epigenetic inhibitors for cancer immunotherapy. DNMT1; BCL11B; T cells Li Yao Wang Jiongliang Zhou Linfu Gu Wenbin Qin Le Peng Dongdong Li Shanglin Zheng Diwei Wu Qiting Long Youguo Yao Yao Lin Shouheng Sun Mingwei Zhang Xiaofei Wang Jie Liu Pengtao Kong Xiangqian Li peng PUBLIC https://creativecommons.org/publicdomain/zero/1.0/ dataset http://www.doi.org/10.1126/sciimmunol.adm8251 Science Data Bank