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STINGing Cancer: Development, Clinical Application, and Targeted Delivery of STING Agonists
Yannick Gabriel Nerdinger1,2,3,4,5, Amanda Katharina Binder1,2,3,4,5, Franziska Bremm1,2,3,4,5
1Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
Abstract:
As cancer incidence continues to rise and conventional therapies remain of limited effectiveness, the search for novel and innovative cancer treatments is ongoing. In recent years, immunotherapies, including checkpoint inhibitors and cell-based approaches such as CAR-T cell therapy, have revolutionized the treatment of cancer. However, response rates even to well-established immunotherapies remain low in several types of cancer. Therefore, various novel immunomodulatory substances are currently under investigation, among them agonists of the intracellular signaling protein STING (STimulator of INterferon Genes). Activation of the STING signaling pathway can alter the cytokine profile within the tumor microenvironment (TME) and reshape the function of various immune cells. STING agonists have yielded promising results in preclinical studies, but this success has not yet been replicated in clinical trials. Consequently, STING agonists are optimized for greater potency and combined with nanotechnologies to enhance biodistribution and achieve sustained accumulation within the TME. This review summarizes a selection of STING agonists evaluated in clinical trials to date and discusses their effects on tumor-infiltration immune cells, especially macrophages. It highlights emerging candidates currently under investigation in preclinical studies, and explores nanotechnological approaches for their combinational use to enhance therapeutic efficacy.
Insights
Novel STING agonists show promise for cancer immunotherapy by modulating the tumor microenvironment and immune cells. Nanotechnology enhances their delivery and efficacy, addressing limitations in current clinical trials.
Area of Science:
- Immunology
- Oncology
- Nanotechnology
Background:
- Rising cancer incidence and limited conventional therapy effectiveness necessitate novel treatments.
- Immunotherapies like checkpoint inhibitors and CAR-T cells have advanced cancer care, but response rates vary.
- STING (STimulator of INterferon Genes) agonists are emerging immunomodulatory agents targeting the tumor microenvironment.
Purpose of the Study:
- To review STING agonists evaluated in clinical trials for cancer treatment.
- To discuss the impact of STING agonists on tumor-infiltrating immune cells, particularly macrophages.
- To explore emerging preclinical STING agonist candidates and nanotechnological strategies for enhanced efficacy.
Main Methods:
- Review of clinical trial data for selected STING agonists.
- Analysis of STING agonist effects on cytokine profiles and immune cell function within the tumor microenvironment.
- Investigation of preclinical studies on novel STING agonists and nanotechnology-based delivery systems.
Main Results:
- STING agonists show potential in preclinical models but clinical translation faces challenges.
- Activation of the STING pathway can alter the tumor microenvironment and reshape immune cell functions.
- Nanotechnology offers a strategy to improve STING agonist potency, biodistribution, and sustained TME accumulation.
Conclusions:
- STING agonists represent a promising avenue for cancer immunotherapy, with ongoing optimization and clinical evaluation.
- Understanding STING agonist interactions with tumor-infiltrating immune cells, especially macrophages, is crucial.
- Combinational approaches using nanotechnology are key to enhancing the therapeutic efficacy of STING agonists.
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