Stimulator of interferon genes (STING) is a cytosolic receptor that senses both exogenous and endogenous cytosolic cyclic dinucleotides (CDNs), activating TBK1/IRF3 (interferon regulatory factor 3), NF-kB (nuclear factor kB), and STAT6 (signal transducer and activator of transcription 6) signaling pathways to induce robust type I interferon and proinflammatory cytokine responses. CDN ligandswere formulatedwith granulocyte-macrophage colony-stimulating factor (GMCSF)-producing cellular cancer vaccines-termed STINGVAX-that demonstrated potent in vivo antitumor efficacy in multiple therapeutic models of established cancer. We found that rationally designed synthetic CDN derivative molecules, including onewith an Rp,Rp dithio diastereomer and noncanonical c[A(2′,5′)pA(3′,5′)p] phosphate bridge zstructure, enhanced antitumor efficacy of STINGVAXinmultiple aggressive therapeuticmodels of established cancer inmice.Antitumor activity was STING-dependent and correlated with increased activation of dendritic cells and tumor antigen-specific CD8+ T cells. Tumors from STINGVAX-treated mice demonstrated marked PD-L1 (programmeddeathligand1)up-regulation, which was associatedwith tumor-infiltrating CD8+IFNγ+ T cells.When combined with PD-1 (programmed death 1) blockade, STINGVAX induced regression of palpable, poorly immunogenic tumors that did not respond to PD-1 blockade alone.
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