cGAS-STING agonist cGAMP enhances natural killer cell-mediated cytotoxicity against gastric cancer cells
WANG Qiang
CHAI Zhixin
DENG Yulu
ZHANG Zhiwei
GONG Ying
GAO Sheng
FENG Pingfeng
Abstract：Objective To explore the molecular mechanism by which cyclic GMP-AMP synthase-stimulator of interferon genes(cGAS-STING)agonists enhance cytotoxicity of natural killer(NK)cells against gastric cancer cells.Methods NK-92 cells were cultured in X-VIVO15 medium to a density of 1×10⁶/mL and treated with 5,1,or 0.2 μmol/L cGAMP for 24 h before co-culture with gastric cancer MGC-803 and MKN-45 cells in RPMI 1640 medium.The expression of IFN-γ in co-cultured NK-92 cells and tumor cells was detected by qPCR and ELISA.The treated NK-92 cells were then co-cultured with the tumor cells labeled with CellTracker™ CM-DiI at different ratios(1:1,2:1,and 4:1),and tumor cell viability and cytotoxicity of NK-92 cells were determined using a dead cell staining kit and flow cytometry-based cytotoxicity assay.Results The cGAS-STING agonist cGAMP dose-dependently enhanced mRNA expression and secretion of the pro-inflammatory cytokines(such as IFN-γ and TNF-α)in NK-92 cells,and NK-92 cells treated with 5 μmol/L cGAMP showed approximately 3-fold increase of IFN-γ and TNF-α levels.cGAMP treatment also upregulated the expression of activating receptors(such as NKp36 and NKp44)on the cell surface and activated the STING-TBK1-IRF3 signaling pathway in NK-92 cells.NK-92 cells pretreated with cGAMP showed increased cytotoxicity against MGC-803 and MKN-45 cells,which could be reversed by treatment with H-151(a STING inhibitor).In tumor-bearing nude mice,combined treatment with cGAMP and NK cells reduced the mass of xenografts by nearly 40%and significantly slowed tumor growth.Conclusion Activating the cGAS-STING pathway can enhance IFN-γ secretion of NK cells to improve their cytotoxicity against gastric cancer cells,suggesting a therapeutic strategy for gastric cancer using NK cells combined with STING agonists.
Keywords：cGAS-STINGGastric cancer cellsNK-92 cellsTumor Immunotherapy
Publication Date：2026-02-20
Online Publishing Date：2026-03-04(First online date of this platform, not the publication date of the document)
Pages：9( 434-442 )