STING-Activating Small Molecular Therapeutics for Cancer Immunotherapy

Immuno-oncology has become a revolutionary strategy for cancer treatment. Therapeutic interventions based on adaptive immunity through immune checkpoint therapy or chimeric antigen receptor (CAR) T cells have received clinical approval for monotherapy and combination treatment in various cancers. Although these treatments have achieved clinical successes, only a minority of cancer patients show a response, highlighting the urgent need to discover new therapeutic molecules that could be exploited to improve clinical outcomes and pave the way for the next generation of immunotherapy. Given the critical role of the innate immune system against infection and cancer, substantial efforts have been dedicated to developing novel anticancer therapeutics that target these pathways. Targeting the stimulator of interferon genes (STING) pathway is a powerful strategy to generate a durable antitumor response, and activation of the adaptor protein STING induces the initiation of transcriptional cascades, thereby producing type I interferons, pro-inflammatory cytokines and chemokines. Various STING agonists, including natural or synthetic cyclic dinucleotides (CDNs), have been developed as anticancer therapeutics. However, since most CDNs are confined to intratumoral administration, there has been a great interest in developing non-nucleotide agonists for systemic treatment. Here, we review the current development of STING-activating therapeutics in both preclinical and clinical stages. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has emerged as a potential target for cancer immunotherapy. Novel STING-activating small molecular therapeutics, including cyclic dinucleotides (CDNs) and non-CDN STING agonists, have been developed to activate the STING pathway for triggering innate immune response. This review introduces the cGAS-STING pathway and highlights several STING agonists and their clinical development. Furthermore, limitations of these agents and their challenges in clinical translation are discussed. image