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STING-Activating Small Molecular Therapeutics for Cancer Immunotherapy
Chuhan Huang1, Tianrui Tong2, Lulu Ren3
1Department of Life Sciences, Imperial College London, London, SW7 2AZ, UK.
Abstract:
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.
Insights
New immuno-oncology therapeutics targeting the STING pathway offer a promising strategy for durable antitumor responses. Research focuses on developing systemic STING agonists beyond current cyclic dinucleotides for broader cancer treatment applications.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Immuno-oncology, including checkpoint inhibitors and CAR T-cells, has transformed cancer treatment but benefits only a subset of patients.
- The innate immune system presents a critical target for novel anticancer therapeutics.
- The stimulator of interferon genes (STING) pathway is a key target for generating robust antitumor immunity.
Purpose of the Study:
- To review the development of STING-activating therapeutics for cancer treatment.
- To highlight the potential of STING agonists in overcoming limitations of current immunotherapies.
- To discuss the transition from intratumoral to systemic STING-activating agents.
Main Methods:
- Review of preclinical and clinical research on STING-activating therapeutics.
- Analysis of cyclic dinucleotides (CDNs) and non-nucleotide STING agonists.
- Evaluation of STING pathway activation mechanisms and outcomes.
Main Results:
- STING pathway activation induces type I interferons, pro-inflammatory cytokines, and chemokines, crucial for antitumor responses.
- Various natural and synthetic cyclic dinucleotides (CDNs) have been developed as STING agonists.
- Development is shifting towards non-nucleotide STING agonists for systemic administration due to limitations of CDNs.
Conclusions:
- STING-activating therapeutics represent a significant advancement in immuno-oncology.
- Further development of systemic STING agonists is crucial for next-generation cancer immunotherapy.
- Targeting the STING pathway holds great promise for improving clinical outcomes in diverse cancers.
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