1. Zebularine potentiates anti-tumor immunity by inducing tumor immunogenicity and improving antigen processing through cGAS-STING pathway.
- Author
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Zhang Y, Zhao H, Deng W, Lai J, Sang K, and Chen Q
- Subjects
- Animals, Female, Humans, Mice, Cell Line, Tumor, Dendritic Cells immunology, Dendritic Cells drug effects, Dendritic Cells metabolism, Mice, Inbred C57BL, Neoplasms immunology, Neoplasms drug therapy, Neoplasms metabolism, Antigen Presentation drug effects, Cytidine analogs & derivatives, Cytidine pharmacology, Membrane Proteins drug effects, Membrane Proteins metabolism, Nucleotidyltransferases drug effects, Nucleotidyltransferases metabolism, Signal Transduction drug effects
- Abstract
DNA methylation is an important epigenetic mechanism involved in the anti-tumor immune response, and DNA methyltransferase inhibitors (DNMTi) have achieved impressive therapeutic outcomes in patients with certain cancer types. However, it is unclear how inhibition of DNA methylation bridges the innate and adaptive immune responses to inhibit tumor growth. Here, we report that DNMTi zebularine reconstructs tumor immunogenicity, in turn promote dendritic cell maturation, antigen-presenting cell activity, tumor cell phagocytosis by APCs, and efficient T cell priming. Further in vivo and in vitro analyses reveal that zebularine stimulates cGAS-STING-NF-κB/IFNβ signaling to enhance tumor cell immunogenicity and upregulate antigen processing and presentation machinery (AgPPM), which promotes effective CD4
+ and CD8+ T cell-mediated killing of tumor cells. These findings support the use of combination regimens that include DNMTi and immunotherapy for cancer treatment., (© 2024. The Author(s).)- Published
- 2024
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