Despite the immense success of immune checkpoint blockade (ICB) in cancer treatment, many tumors, including melanoma, exhibit innate or adaptive resistance. Tumor-intrinsic T-cell deficiency and T-cell dysfunction have been identified as essential factors in the emergence of ICB resistance. Here, we found that protein arginine methyltransferase 1 (PRMT1) expression was inversely correlated with the number and activity of CD8+ T cells within melanoma specimen. PRMT1 deficiency or inhibition with DCPT1061 significantly restrained refractory melanoma growth and increased intratumoral CD8+ T cells in vivo. Moreover, PRMT1 deletion in melanoma cells facilitated formation of double-stranded RNA derived from endogenous retroviral elements (ERV) and stimulated an intracellular interferon response. Mechanistically, PRMT1 deficiency repressed the expression of DNA methyltransferase 1 (DNMT1) by attenuating modification of H4R3me2a and H3K27ac at enhancer regions of Dnmt1, and DNMT1 downregulation consequently activated ERV transcription and the interferon signaling. Importantly, PRMT1 inhibition with DCPT1061 synergized with PD-1 blockade to suppress tumor progression and increase the proportion of CD8+ T cells as well as IFNγ+CD8+ T cells in vivo. Together, these results reveal an unrecognized role and mechanism of PRMT1 in regulating antitumor T-cell immunity, suggesting PRMT1 inhibition as a potent strategy to increase the efficacy of ICB. Significance: Targeting PRMT1 stimulates interferon signaling by increasing expression of endogenous retroviral elements and double-stranded RNA through repression of DNMT1, which induces antitumor immunity and synergizes with immunotherapy to suppress tumor progression.

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.

UHRF1 maintains DNA methylation by recruiting DNA methyltransferases to chromatin. In mouse, these dynamics are potently antagonized by a natural UHRF1 inhibitory protein STELLA, while the comparable effects of its human ortholog are insufficiently characterized, especially in cancer cells. Herein, we demonstrate that human STELLA (hSTELLA) is inadequate, while mouse STELLA (mSTELLA) is fully proficient in inhibiting the abnormal DNA methylation and oncogenic functions of UHRF1 in human cancer cells. Structural studies reveal a region of low sequence homology between these STELLA orthologs that allows mSTELLA but not hSTELLA to bind tightly and cooperatively to the essential histone-binding, linked tandem Tudor domain and plant homeodomain (TTD-PHD) of UHRF1, thus mediating ortholog-specific UHRF1 inhibition. For translating these findings to cancer therapy, we use a lipid nanoparticle (LNP)-mediated mRNA delivery approach in which the short mSTELLA, but not hSTELLA regions are required to reverse cancer-specific DNA hypermethylation and impair colorectal cancer tumorigenicity.