cyclic-guanosine-monophosphate-adenosine-monophosphate and pyrimidin-2-one-beta-ribofuranoside

DNA methylation abnormality is closely related to tumor occurrence and development. Chemical inhibitors targeting DNA methyltransferase (DNMTis) have been used in treating cancer. However, the impact of DNMTis on antitumor immunity has not been well elucidated. In this study, we show that zebularine (a demethylating agent) treatment of cancer cells led to increased levels of interferon response in a cyclic guanosine monophosphate-AMP (cGAMP) synthase (cGAS)- and stimulator of interferon genes (STING)-dependent manner. This treatment also specifically sensitized the cGAS-STING pathway in response to DNA stimulation. Incorporation of zebularine into genomic DNA caused demethylation and elevated expression of a group of genes, including STING. Without causing DNA damage, zebularine led to accumulation of DNA species in the cytoplasm of treated cells. In syngeneic tumor models, administration of zebularine alone reduced tumor burden and extended mice survival. This effect synergized with cGAMP and immune checkpoint blockade therapy. The efficacy of zebularine was abolished in nude mice and in cGAS

Topics: Administration, Oral; Animals; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cytidine; Drug Synergism; Humans; Killer Cells, Natural; Melanoma, Experimental; Membrane Proteins; Mice; Mice, Nude; Nucleotides, Cyclic; Nucleotidyltransferases; Promoter Regions, Genetic; THP-1 Cells; Tumor Microenvironment; Xenograft Model Antitumor Assays