Tumor endothelial cells (TECs) have distinct characteristics that differentiate them from ordinary endothelial cells. These differences include cytogenetic abnormalities such as aneuploidy and abnormal centrosomes, which are more similar to tumor cells (Maishi, Annan, Kikuchi, Hida, & Hida, 2019; Qiu et al., 2017). Moreover, TECs undergo a series of epigenetic changes, represented by DNA methylation. Tumor blood vessels are primarily composed of TECs, which provide nutrients and oxygen to the tumor while also assisting in tumor metastasis.

DNA methylation is usually a typical epigenetic modification that involves various biological functions, including gene silencing, chromatin remodeling, and embryonic development (Papanicolau-Sengos & Aldape, 2022). In addition, DNA methylation is inseparable from the participation of DNA methyltransferases, including DNMT1, DNMT2, DNMT3A, DNMT3B, and DNMT3L, causing the methyltransferase to move from s-adenosyl methionine (SAM) to cytosine C5 (Petryk, Bultmann, Bartke, & Defossez, 2021). However, DNMT inhibitors (DNMTis) can block the activity of DNMTs, leading to the re-expression of silenced tumor suppressor genes (Castillo-Aguilera, Depreux, Halby, Arimondo, & Goossens, 2017). Several DNMTis, such as azacytidine (AZA) and decitabine (DAC), have been approved by the FDA for the treatment of acute myeloid leukemia (AML) (Dhillon, 2020). Therefore, the development and evaluation of DNMTis have become an important strategy for cancer treatment.

Tumor angiogenesis and endothelial cell (EC) transformation are crucial to tumor metastasis. Due to the growth factors secreted by tumor cells or chronic stimulation caused by hypoxia, normal endothelial cells (NECs) are transformed into TECs. In contrast to NECs, TECs have major changes at the morphological and molecular levels, such as varying size and shape and pores in the newly formed blood vessels, which can provide the conditions for tumor metastasis (Lidonnici, Santoro, & Oberkersch, 2022). The sites rich in CpG dinucleotides are called CpG islands. Hypomethylation of cancer-related genes and hypermethylation of normal tumor suppressor gene (TSG) CpG islands exist in TECs (Ciesielski et al., 2020). Hellebrekers et al. found that 81 downregulated genes in TECs had epigenetic changes, which can be re-expressed by the combination treatment of DNMTis and histone deacetylase inhibitors (HDACis) (Hellebrekers et al., 2007). Their data provide mechanisms for the epigenetic regulation of tumor angiogenesis and the vasopressor effects of DNMTis and HDACis. Epigenetic changes in TECs not only promote the formation of tumor blood vessels but also secrete IL-6, IL-8, TGF-β, and other molecules to induce tumor cell proliferation and metastasis (Pirtskhalaishvili & Nelson, 2000).

Antitumor angiogenesis, especially in TECs, is a new targeted therapeutic strategy. Considering the large amount of abnormal DNA methylation in TECs, the combination of DNMTis with other antitumor angiogenesis drugs or radiotherapy has achieved great progress in cancer therapy (Ciesielski et al., 2020). A phase III clinical trial (NCT00934440) registered on the clinicaltrials.gov website (https://clinicaltrials.gov/) investigated a combination therapy of 5-nitrocytosine and bevacizumab in the treatment of 11 patients with renal cell carcinoma. The results of the trial showed that this combination therapy has lower toxicity and improved efficacy.

Given the toxicity and untargeted nature of DNMTis, it is crucial to identify vectors that can precisely deliver DNMTis to TEC sites. Vectors such as folic acid, monoclonal antibodies, and aptamers are expected to play a vital role in the accurate application of DNMTis in TEC-targeted treatment.

In this review, we discuss the unique characteristics of TECs, DNA methylation, and the role of DNMTis in TEC therapy. We also summarize the latest research and clinical progress in TEC combination therapy. Finally, we highlight the potential of vector-based delivery systems and discuss their future development in TEC therapy.