Authors: Yao Li, Jiongliang Wang, Linfu Zhou, Wenbin Gu, Le Qin, Dongdong Peng, Shanglin Li, Diwei Zheng, Qiting Wu, Youguo Long, Yao Yao, Shouheng Lin, Mingwei Sun, Xiaofei Zhang, Jie Wang, Pentao Liu, Xiangqian Kong, Peng Li
Published: 2025-03-21
DOI: 10.1126/sciimmunol.adm8251
Source: Full article
Inactivation of the transcription factor BCL11B reprograms T cells into induced-T-to-NK cells (ITNKs). However, it remains unclear how BCL11B suppresses natural killer (NK) cell transcriptional programs. Here, we identified that the DNA methyltransferase DNMT1 physically interacts with BCL11B, increasing BCL11B stability and the fidelity of DNA methylation maintenance for NK cell–related genes, thereby repressing their expression. Moreover, DNMT1 maintains the epigenetic silencing of a distinct subset of NK cell–related genes independent of BCL11B. DNMT1 inhibition or depletion reprograms T cells and chimeric antigen receptor (CAR)–T cells into NK-like cells that exhibit more robust antitumor effects than BCL11B-deficient ITNKs and parental CAR-T cells. Moreover, H3K27me3 (trimethylation of histone 3 lysine 27) synergizes with DNA methylation to repress NK cell–related pathways, and combined EZH2 (enhancer of zeste homolog 2) and DNMT1 inhibition potentiates 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 cells with epigenetic inhibitors for cancer immunotherapy.