biostudies-literatureWang YTsinghua UniversityCenter for Life SciencesBeijing Frontier Research Center for Biological Structure, Tsinghua UniversityNational Natural Science Foundation of ChinaBeijing Natural Science Foundation111038https://www.ebi.ac.uk/biostudies/studies/S-EPMC12907715biostudies-literatureUnknown302(2)The cGAS-STING signaling pathway is a crucial innate immune pathway that senses cytosolic DNA. Pharmacological activation of the cGAS-STING pathway might be a promising strategy for cancer immunotherapy. Here, we report that the cGAS-STING pathway is a new target of telatinib, an orally available vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor that has been investigated in clinical trials. In this study, we demonstrated that telatinib induced innate immune responses in a STING-dependent manner. In addition, we determined the crystal structure of STING bound to a telatinib analog, revealing the molecular interactions underlying STING activation. Moreover, we showed that telatinib-mediated STING activation contributed to the antitumor effects in tumor-bearing mouse models. IThe Journal of biological chemistryActivation of stimulator of interferon genes (STING) and inhibition of vascular endothelial growth factor receptor (VEGFR) by telatinib induce antitumor activity.PMC12907715320708758224107422101036Z220018Yang JChen KZhang ZLiu PHan JWang YZhang CHou YCheng YMou LFan SDai YfalseActivation of stimulator of interferon genes (STING) and inhibition of vascular endothelial growth factor receptor (VEGFR) by telatinib induce antitumor activity.The cGAS-STING signaling pathway is a crucial innate immune pathway that senses cytosolic DNA. Pharmacological activation of the cGAS-STING pathway might be a promising strategy for cancer immunotherapy. Here, we report that the cGAS-STING pathway is a new target of telatinib, an orally available vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor that has been investigated in clinical trials. In this study, we demonstrated that telatinib induced innate immune responses in a STING-dependent manner. In addition, we determined the crystal structure of STING bound to a telatinib analog, revealing the molecular interactions underlying STING activation. Moreover, we showed that telatinib-mediated STING activation contributed to the antitumor effects in tumor-bearing mouse models. I2025-01-01T00:00:00Z2025 Dec2026-07-16T05:02:06.715Z2026-07-09T10:36:31.785ZS-EPMC129077154138097210.1016/j.jbc.2025.111038