Anti-triple-negative breast cancer metastasis efficacy and molecular mechanism of the STING agonist for innate immune pathway

Abstract

AbstractBackground With high recurrence and metastatic rates, triple-negative breast cancer (TNBC) has few therapy choices. The innate immune stimulator of interferon genes protein (STING) pathway has emerged as a critical foundation for improving anticancer immunotherapy. Although 2’,3’-cGAMP has been shown to have therapeutic potential as a STING agonist in subcutaneous solid tumour treatments in mice, the effect of cGAMP in metastatic malignancies has received less attention.Methods Bioluminescence imaging technology was applied to monitor TNBC tumour cell metastasis in living mice. Serum biochemical test and blood routine examination of mice were used to demonstrate cGAMP administration had no toxicity. The activation of DCs and CD8+ T cells was demonstrated by flow cytometry. The pharmacological mechanism of cGAMP for suppressing breast tumour metastasis was also explored.Results cGAMP treatment substantially suppressed tumour development and metastasis without adverse effects. cGAMP activated the cGAS-STING-IRF3 pathway, which modified the tumour immune milieu to reverse the Epithelial-Mesenchymal Transition (EMT) and PI3K/AKT pathways and prevent tumour metastasis. It was postulated and proven that cGAMP had a pharmacological mechanism for reducing breast tumour metastasis.Conclusion The findings suggest that cGAMP could be useful in the immunotherapy of immune-insensitive metastatic breast cancer.

Keywords

• Metalloenzyme cGAS
• cGAMP
• STING pathway
• metastatic breast cancer
• EMT
• PI3K/AKT pathways