Considerations for the delivery of STING ligands in cancer immunotherapy

Several studies have shown the importance of the cGAS-STING pathway in antigen-presenting cells for anti-cancer immunity. Cyclic GMP-AMP (cGAMP) - STING ligand is a negatively charged dinucleotide prone to degradation by hydrolases. Once administered in its soluble form, high doses are needed which in turn may cause side effects such as T cell apoptosis. Moreover, due to its negative charge, transfection of cGAMP into negatively-charged membrane cells is hampered. In order to achieve successful transfection and protection from enzymatic degradation there is a need for a suitable carrier for cGAMP. In this review, we therefore describe currently reported carriers for cGAMP, and correlate their characteristics to the effect they cause. To achieve targeted delivery to the tumor microenvironment, the route of administration and physicochemical parameters of the particles (containing a carrier and cGAMP) such as size and charge need to be determined. Therefore, the choice of the particle formulation and its impact on the preclinical outcome will be discussed.