Introduction: The innate immune sensing STING pathway has emerged as a potential therapeutic target to boost antitumor immune responses. However, STING resides in the cytoplasm, and its agonist cGAMP is a dinucleotide that is difficult to deliver intracellularly. Since microbubbles are known to deliver payloads directly into the cytoplasm under ultrasound (sonoporation), we've developed and optimized a Microbubble (MB)-assisted UltraSound (US)-guided Immunotherapy of Cancer (MUSIC) platform to activate STING for treatment of primary and metastatic tumors. Materials and methods: Cationic polymer MBs were targeted to CD11b on the surface of macrophages in vitro and sonoporated to deliver their cGAMP payload directly into the cell cytosol to activate STING, which was validated by western blot, qRT-PCR, and ELISA. For in vivo studies, C57Bl/6 and Balb/c mice were implanted with E0771 and Luc-4T1 breast cancer cells respectively. Primary tumors were treated when they were large enough (E0771) or when they metastasized to the lungs (Luc-4T1) using MUSIC following intratumoral injection. Tumor volumes and luciferase activity were measured over time to assess therapeutic responses. Results and Discussion: In both syngeneic breast cancer models, MUSIC treatment showed dramatic inhibition of tumor growth, increased mice survival, and a greater percentage of tumor-free mice compared to cGAMP alone. MUSIC treatment also resulted in an 11-fold decrease in metastatic burden when compared to cGAMP alone. These results suggest that MUSIC treatment effectively activates STING in vivo, creating a systemic anti-tumor immune response.

Using MUSIC to stimulate the immune system

ACS Fall 2021

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