Delivery strategies for STING agonists

Activation of the stimulator of interferon genes (STING) pathway through cyclic dinucleotides (CDNs) has been explored extensively as potent vaccine adjuvants against infectious diseases as well as to increase tumor immunogenicity toward cancer immunotherapy in tumors. Despite the promise of CDNs as immune adjuvants, they suffer from several limitations: (1) CDNs exhibit fast clearance from the injection site, which may induce systemic toxicity, (2) naturally derived CDNs are susceptible to enzymatic degradation, which can lower the efficacy of adjuvanticity potential, and (3) CDNs have inefficient intracellular transport properties due to limited endosomal escape or reliance on the expression of a specific transporter protein. To address these challenges, over the last decade, a myriad of synthetic vehicles, including liposomes, polymers, and other nanoparticle platforms, have been developed to improve the bioavailability and therapeutic efficacy of STING agonists in preclinical mouse models. In this review, we will first summarize recent progress in the fundamental biology of the STING pathway in cancer and immunology, and then review advances in developing new STING agonist compounds and delivery strategies to overcome many challenges in the field.