BCL11B ablation reprograms T cells into induced-T-to-NK cells (ITNKs).Mouse ITNKs potently killed leukemia and solid tumor cells. Recently, we also reported that human ITNKs, derived from CRISPR-based BCL11B-ablated T cells, exhibited robust antitumor activity in xenografts. In a preliminary clinical trial (NCT: 03882840), infusion of ITNKs resulted in partial remission or tumor stabilization without severe adverse effects in six out of nine patients with refractory and advanced solid tumors. However, it remains unclear how BCL11B suppresses NK cell programs. Here, we uncover a physical interaction between DNMT1 and BCL11B that increases BCL11B protein stability and the fidelity of DNA methylation maintenance for NK cell-related genes and represses their expression. 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 CAR T cells into NK-like cells that 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 EZH2 inhibitor (EZH2i) and DNMT1i 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. Our study may reveal a new mechanism: HMAs activate NK cell program in T cells and augment their antitumor activity. Moreover, based on preclinical characterizations of HMAs-induced NK-like cells, we are conducting an investigator-initiated trial of treating patients with solid tumors at terminal stages with these NK-like cells.