Cancer therapies targeting the STING pathway

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Abstract

Modern oncology needs to develop and implement antineoplastic agents that provide sustained remission without serious side effects. Immunotherapy and targeted therapy agents that activate innate immunity may address this issue. The stimulator of interferon genes (STING), an intracellular protein, mediates the synthesis of type I interferons, which have antiviral, antitumor, and antiproliferative properties. The multifaceted effects of interferons may be beneficial in cancer therapy. However, potential side effects of systemic interferon therapy underlie the need for the methods of stimulating them locally in the tumor nodule by targeting the STING pathway. STING is directly activated by the cyclic dinucleotide cGAMP. It is synthesized by the cyclic GMP-AMP synthase (cGAS) from adenosine triphosphate and guanosine triphosphate. However, cGAMP cannot be used as a therapeutic agent because it is unstable and only persists in the cell for a short period of time before being hydrolyzed. Therefore, researchers all over the world are working to synthesize new activators of the STING pathway. In cancer therapy, using STING activators as part of an immunoconjugate for targeted delivery to the tumor nodule is considered more effective. A monoclonal antibody against a tumor-specific antigen is the second component of the immunoconjugate. Given the high risk of tumor cell resistance to cytostatic drugs commonly used in current clinical practice, an immunoconjugate with a STING activator may provide advantages over existing therapies. Several immunoconjugates have already been tested in preclinical studies and are considered promising for drug development. However, further research is needed to study the properties of new compounds and improve their efficacy and tolerability. The search was performed in PubMed, eLIBRARY.RU, Google Scholar, NCBI ClinicalTrials, and PubChem and included publications from June to August 2025. The following search terms were used: STING protein, cGAS protein, cGAS-STING pathway, IFN-β, interferon-based treatment, type I IFN induction, antibody-drug conjugate, STING activation, STING agonist, and HER2-targeted therapies.

About the authors

Anastasia O. Karimova

Blokhin National Medical Research Center of Oncology; National Research University Higher School of Economics

Author for correspondence.
Email: a.karimova@ronc.ru
ORCID iD: 0009-0000-0317-9948
SPIN-code: 8054-2753
Russian Federation, Moscow; Moscow

Yana O. Sadovskaya

Blokhin National Medical Research Center of Oncology

Email: ja.sadovskaja@ronc.ru
ORCID iD: 0009-0009-7115-7797
SPIN-code: 8572-7717
Russian Federation, Moscow

Olga N. Solopova

Blokhin National Medical Research Center of Oncology; National Research University Higher School of Economics

Email: o.solopova@ronc.ru
ORCID iD: 0000-0002-5465-6094
SPIN-code: 2807-7709

Cand. Sci. (Biology)

Russian Federation, Moscow; Москва

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