Liposomal Delivery Enhances Immune Activation by STING Agonists for Cancer Immunotherapy

Overcoming the immunosuppressive tumor microenvironment (TME) is critical to realizing the potential of cancer immunotherapy strategies. Agonists of stimulator of interferon genes (STING), a cytosolic immune adaptor protein, have been shown to induce potent antitumor activity when delivered into the TME. However, the anionic properties of STING agonists make them poorly membrane permeable, and limit their ability to engage STING in the cytosol of responding cells. In this study, cationic liposomes with varying surface polyethylene glycol levels are used to encapsulate 2'3' cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) to facilitate its cytosolic delivery. In vitro studies with antigen-presenting cells (APCs) revealed that liposomal formulations substantially improve the cellular uptake of cGAMP and proinflammatory gene induction relative to free drug. Liposomal encapsulation allows cGAMP delivery to metastatic melanoma tumors in the lung, leading to antitumor activity, whereas free drug produces no effect at the same dose. Injection of liposomal cGAMP into orthotopic melanoma tumors shows retention of cGAMP at the tumor site and colocalization with tumor-associated APCs. Liposomal delivery induces regression of injected tumors and produces immunological memory that protects previously treated mice from rechallenge with tumor cells. These results show that liposomal delivery improves STING agonist activity, and could improve their utility in clinical oncology.