VEGFR2 inhibition potentiates STING-mediated antitumor immunity

STING bridges innate and adaptive immunity to exert potent antitumor effects, and its agonists play emerging roles in combination therapies with tyrosine kinase inhibitors (TKIs). However, the interaction between STING and receptor tyrosine kinases (RTKs) remains incompletely understood. Here, we identify VEGFR2 as a negative regulator of cGAMP-STING signaling. Upon cGAMP stimulation, both STING and VEGFR2 are activated. Activated VEGFR2 recruits and activates AKT1 to attenuate STING activation. Conversely, STING suppresses VEGFR2 phosphorylation, establishing a reciprocal inhibitory feedback loop. A cell-based screen reveals that the VEGFR2 inhibitor Ki8751 not only relieves VEGFR2-AKT1-mediated suppression but also activates MyD88-dependent NF-κB signaling to further amplify STING responses. Additionally, we show that Ki8751 synergizes with cGAMP to elicit robust, STING-dependent antitumor immunity in vivo. Our findings identify the VEGFR2-STING regulatory axis and provide a mechanistic rationale for co-targeting VEGFR2 and STING to improve cancer immunotherapy.