STING activation and overcoming the challenges associated with STING agonists using ADC (antibody-drug conjugate) and other delivery systems.

In current immunotherapy cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway considered as most focused area after CAR-T cell. Exploitation of host immunity against cancer using STING agonists generates the most interest as a therapeutic target. Classically cGAS activation through cytoplasmic DNA generates 2'3'cGAMP that is naturally identified STING agonist. Activation of STING leads to activation of type-1 interferon response and pro-inflammatory cytokines through TBK/IRF-3, TBK/NF-κB pathways. Pro-inflammatory cytokines attract immune cells to the tumor microenvironment and type-1 interferon exposes tumor antigens to T cells and NK cells, which leads to the activation of cellular immunity against tumor cells and eliminates tumor cells. Initially bacterial-derived c-di-AMP and c-di-GMP were identified as CDNs (Cyclic-dinucleotide) STING agonists. Moreover, chemically modified CDNs and completely synthetic STING agonists have been developed. Even though the breakthrough preclinical development none of the STING agonists were approved the by FDA for cancer therapy. All identified natural CDNs have poor pharmacokinetic properties due to high hydrophilicity and negative charge. Moreover, phosphodiester bonds in CDNs are most vulnerable to enzymatic degradation. Synthetic STING agonists have an off-target effect that generates autoimmunity and cytokine storm. STING agonist needs to improve for pharmacokinetics, efficacy, and safety. In this scenario delivery systems can overcome the challenges associated with STING agonists. Here, we highlight the ways of STING agonisms as direct and indirect, and further, we also discuss the existing STING agonists associated challenges and ongoing efforts for delivery of STING agonists in the tumor microenvironment (TME) via different non-targeted carriers like Nanoparticle, Hydrogel, Micelle, Liposome. We also discussed the most advanced targeted deliveries of ADC (Antibody-drug conjugate) and aptamers-based delivery.