Universal STING mimic boosts antitumour immunity via preferential activation of tumour control signalling pathways.
Ying WangSirui LiMengying HuYuchen YangEllie McCabeLillian ZhangAndrew M WithrowJenny P Y TingRihe LiuPublished in: Nature nanotechnology (2024)
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.
Keyphrases
- dendritic cells
- immune response
- binding protein
- regulatory t cells
- poor prognosis
- squamous cell carcinoma
- small cell lung cancer
- endothelial cells
- stem cells
- cell proliferation
- drug delivery
- reactive oxygen species
- dna methylation
- lps induced
- induced apoptosis
- papillary thyroid
- anti inflammatory
- ultrasound guided
- lymph node metastasis
- replacement therapy
- childhood cancer
- genome wide identification