An epigenetic switch in vascular phenotype augments anti-tumor immunity

The abnormal tumor vasculature can present a barrier to the infiltration of anti-tumor immune cells, which impairs immune surveillance and response to immunotherapy. Here, we show that genetically deleting the epigenetic factor DNA methyltransferase 1 (Dnmt1) in endothelial cells (ECs) reduces angiogenesis while imparting profound changes to the tumor immune microenvironment (TIME), including increased proportions of CD4⁺ memory T cells and NK cells. Depleting CD4⁺ T cells, or blocking lymphocyte egress from the lymph nodes, rescues tumor growth in mice with conditional deletion of Dnmt1 in ECs (Dnmt1^iECKO) and dramatically shortens overall survival, whereas NK cells are dispensable. Tumors implanted in Dnmt1^iECKO mice show reduced vascular branching, elevated expression of VCAM1, increased vessel-associated T cells, and a shift in vascular specification, including increased proportions of immune-permissive post-capillary venules (PCVs) and interferon-stimulated ECs (IFN-ECs). Deleting Dnmt1 in EC cultures strikingly potentiates responses to combinations of IFNγ and TNFα and, notably, up-regulates important T-cell co-stimulatory molecules for memory CD4⁺ T cells, including Icosl, Cd40, and Tnfsf4. Finally, immune checkpoint blockade (ICB) administered to Dnmt1^iECKO mice with experimental melanoma lung metastasis reduces tumor burden, with some mice showing tumor eradication. Our findings identify endothelial Dnmt1 as a key regulator of vascular-mediated anti-tumor immunity, providing a rationale for integrating epigenetic modulation of the vasculature with cancer immunotherapy regimens.