Universal STING Mimic Boosts Antitumour Immunity via Preferential Activation of Tumour Control Signalling Pathways

The efficacy of stimulator of interferon genes (STING) agonists is compromised by various factors, primarily inefficient intracellular delivery, low/lack of endogenous STING expression in many tumours and a complex balance between tumour control and progression. Here, we report a universal STING mimic (uniSTING) based on a polymeric architecture. The uniSTING activates STING signalling in a range of mouse and human cell types, independent of endogenous STING expression, and selectively stimulates tumour control IRF3/IFN-I pathways, but not tumour progression NF-?B pathways. Intratumoural or systemic injection of uniSTING-mRNA via lipid nanoparticles (LNP) results in potent anti-tumour efficacy across established and advanced metastatic tumour models, including triple negative breast cancer, lung cancer, melanoma and orthotopic/metastatic liver malignancies. Furthermore, uniSTING displays an effective antitumour response superior to 2'3'-cGAMP and ADU-S100. By favouring IRF3/IFN-I activity over the pro-inflammatory NF-?B signalling pathway, uniSTING promotes dendritic cell maturation and antigen specific CD8+ T cell responses. Extracellular vesicles released from uniSTING-treated tumour cells further sensitise dendritic cells via exosome containing miRNAs that reduced the immunosuppressive Wnt2b and a combination of LNP-uniSTING-mRNA with a-Wnt2b antibodies synergistically inhibit tumour growth and prolong animal survival. Collectively, these results demonstrate the LNP-mediated delivery of uniSTING-mRNA as a strategy to overcome the current STING therapeutic barriers, particularly for the treatment of multiple cancer types in which STING is downregulated or absent. Overall design: To investigate the function of uniSTING in the regulation of Type I IFN signaling pathways, we performed RNA-seq on 4T1 tumor cells post treatments with either uniSTING mRNA or Mock (EGFP) mRNA. Moreover, the uniSTING's effect on downstream pathways in an unbiased fashion was also examined on 4T1 tumor cells. The gene expression profiling analysis was performed using the RNA-seq data of 4T1 tumor cells after indicated treatments above.