Universal STING mimic boosts antitumour immunity via preferential activation of tumour control signalling pathways

Ying Wang; Sirui Li; Mengying Hu; Yuchen Yang; Ellie McCabe; Lillian Zhang; Andrew M Withrow; Jenny P-Y Ting; Rihe Liu

doi:10.1038/s41565-024-01624-2

Universal STING mimic boosts antitumour immunity via preferential activation of tumour control signalling pathways

Nat Nanotechnol. 2024 Mar 13. doi: 10.1038/s41565-024-01624-2. Online ahead of print.

Authors

Ying Wang^#¹, Sirui Li^#^{2

3}, Mengying Hu⁴, Yuchen Yang⁵, Ellie McCabe¹, Lillian Zhang¹, Andrew M Withrow¹, Jenny P-Y Ting^{6

7}, Rihe Liu^{8

9

10}

Affiliations

¹ Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
² Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴ Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
⁵ State Key Laboratory of Biocontrol, School of Ecology, Sun Yat-sen University, Guangzhou, China.
⁶ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. jenny_ting@med.unc.edu.
⁷ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. jenny_ting@med.unc.edu.
⁸ Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. rliu@email.unc.edu.
⁹ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. rliu@email.unc.edu.
¹⁰ Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. rliu@email.unc.edu.

^# Contributed equally.

PMID: 38480836
DOI: 10.1038/s41565-024-01624-2

Abstract

The efficacy of STING (stimulator of interferon genes) agonists is due to 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. 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-κB pathways. Intratumoural or systemic injection of uniSTING-mRNA via lipid nanoparticles (LNPs) results in potent antitumour 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 proinflammatory NF-κB signalling pathway, uniSTING promotes dendritic cell maturation and antigen-specific CD8⁺ T-cell responses. Extracellular vesicles released from uniSTING-treated tumour cells further sensitize dendritic cells via exosome-containing miRNAs that reduced the immunosuppressive Wnt2b, and a combination of LNP-uniSTING-mRNA with α-Wnt2b antibodies synergistically inhibits tumour growth and prolongs 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.

Abstract

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