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After development for more than ten years, stimulator of interferon genes (STING), a representative of pattern recognition receptors (PRRs), is now entering the stage of widespread applications. Along with the evolution of STING agonists of cyclic dinucleotides (CDNs) and non‐nucleotide molecules, the stability of agonists has been improved. However, their poor performance in clinical trials triggers urgent demands for highly effective delivery strategies to further improve the cellular permeability, tissue targetability and retention. In this review, we summarized the recent progress of STING agonists applications and delivery strategies with a focus on the biocompatible platforms of peptide, protein and biomembrane, providing a novel vision for the STING field and future direction. [ABSTRACT FROM AUTHOR]

Since being discovered in 2008, the STING (stimulator of interferon genes) pathway has gradually been recognized as a central and promising target for immunotherapy. The STING pathway can be stimulated by cyclic dinucleotides (CDNs), leading to the type I interferons (IFN) production for immunotherapy for cancer or other diseases. However, the negative charges, hydrophilicity, and instability of CDNs have hindered their further applications. In addition, chronic activation of the STING pathway has been found to be involved in autoimmune diseases as IFN overproduction. Thus, research and development of STING agonists and inhibitors has been a hot field for the treatment of several diseases. The past several years, especially 2018, has seen increasingly rapid advances in this field. Here, this review summarizes the synthesis and modification of CDNs, the identification of nonnucleotide agonists, the recent progress in delivery systems and the medical applications, such as personalized vaccine adjuvants, in detail. In addition, in this review, we summarize the STING inhibitors' advances from two aspects, covalent, and noncovalent inhibitors. [ABSTRACT FROM AUTHOR]

This triggered urgent demands for highly effective delivery strategies to improve the cellular permeability, tissue targetability and retention of STING agonists. Along with the development of the STING pathway, more and more agonists have been adopted by Novartis, Bristol-Myers Squibb, Merck and so on for the treatment of advanced or metastatic tumors in clinical trials. However, STING agonists cyclic dinucleotides (CDNs) displayed almost zero efficacy in clinical trials, likely due to poor cellular permeability and rapid diffusion despite intratumoral injection. [Extracted from the article]

Cyclic dinucleotides (CDNs), agonists of stimulator of interferon genes (STING), are promising agents for immunotherapy. However, the application of CDNs has been limited by their instability and low transmembrane efficiency. Here, we introduced a conjugated adjuvant of STING and TLR1/2, Pam 3 CSK 4 -CDG SF . Conjugating CDG SF with Pam 3 CSK 4 increased the stability and intracellular delivery. In addition, by synergistically activating the STING and TLR pathways, Pam 3 CSK 4 -CDG SF was able to enhance immune activation. Both humoral and cellular immune responses were triggered by Pam 3 CSK 4 -CDG SF plus OVA (V4), and tumor growth was significantly inhibited after V4 administration. More importantly, V4 can also boost the antigen-specific CD8+ T cell response for cancer cell killing. Thus, the conjugated STING and TLR1/2 agonist Pam 3 CSK 4 -CDG SF can serve as a potent adjuvant for vaccine construction to augment antitumor immunotherapy.