Endothelial STING-JAI(1 interaction promotes tumor vasculature normalization and antitumor immunity

Stimulator of interferon genes (STING) agonists have been developed and tested in clinical trials for their antitumor activity. However, the specific cell population(s) responsible for such STING activation-induced antitumor immunity have not been completely understood. In this study, we demonstrated that endothelial STING expression was critical for STING agonist- induced antitumor activity. STING activation in endothelium promoted vessel normalization and CD8+ T cell infiltration - which required type I IFN (IFN-I) signaling- but not IFN-gamma or CD4+ T cells. Rather than an upstream adaptor for inducing IFN-I signaling, STING acted downstream of interferon-alpha/beta receptor (IFNAR) in endothelium for the JAI(1-STAT signaling activation. Mechanistically, IFN-I stimulation induced JAI(1-STING interaction and promoted JAI(1 phosphorylation, which involved STING palmitoylation at the Cysteine 91 site but not its C-terminal tail (CTT) domain. Endothelial STING and JAI(1 expression was significantly associated with immune cell infiltration in patients with cancer, and STING palmitoylation level correlated positively with CD8+ T cell infiltration around STING-positive blood vessels in tumor tissues from patients with melanoma. In summary, our findings uncover a previously unrecognized function of STING in regulating JAI(1/STAT activation downstream of IFN-I stimulation and provide a new insight for future design and clinical application of STING agonists for cancer therapy.