Preclinical efficacy of a systemically-administered, second-generation STING agonist that promotes anti-tumour immunity in combination with radiotherapy
BACKGROUND: As potent triggers of innate immunity, STING agonists hold promise as active immunotherapeutic agents for cancer treatment. Second-generation STING agonists, suitable for systemic delivery, are being investigated in preclinical research and have entered clinical trials. Here, the novel synthetic STING agonist, BI-1703880 (STINGa), was investigated for anti-tumour and immunological effects. METHODS: We used human and murine immune and tumour cells to examine the effects of STINGa in vitro, and preclinical cancer mouse models to investigate effects in vivo. RESULTS: We show that STINGa activates the STING pathway and results in a transient and dose-dependent upregulation and secretion of interferons and proinflammatory cytokines in vitro and in vivo. We show that intravenous administration of repeated dosing with low-dose STINGa is well tolerated. We report that radiotherapy (RT) and STING agonism synergises to generate innate immune cell and CD8+ T cell responses that control tumour growth. RT/STINGa upregulated PD-L1, PD-1 and CTLA-4 in the tumour microenvironment. Our findings show that combining RT/STINGa with immune checkpoint inhibitors further increases therapeutic benefit. CONCLUSIONS: Our data confirm STING as a therapeutic target in cancer and support the clinical development of BI1703880 STING agonist, thereby suggesting radiotherapy as a potential combination for enhancing anti-tumour efficacy.
Authors
- Justin Weir (ORCID: https://orcid.org/0009-0009-4363-3135)
- Elizabeth S. Appleton (ORCID: https://orcid.org/0000-0002-8794-3428)
- Naomi Guppy (ORCID: https://orcid.org/0000-0003-1004-3605)
- Charleen Chan Wah Hak (ORCID: https://orcid.org/0000-0002-6386-5699)
- Emmanuel Christian Patin (ORCID: https://orcid.org/0000-0001-5390-5733)
- Lisa C. Hubbard (ORCID: https://orcid.org/0009-0007-1540-4445)
- Antonio Rullan (ORCID: https://orcid.org/0000-0002-7365-9629)
- Thorsten K. Oost (ORCID: https://orcid.org/0009-0000-7432-5500)
- Isaac Dean (ORCID: https://orcid.org/0000-0002-4750-5335)
- Shane Foo (ORCID: https://orcid.org/0000-0001-6295-7404)
- Holly Baldock (ORCID: https://orcid.org/0000-0003-2751-4549)
- Kevin Morse (ORCID: https://orcid.org/0000-0002-2296-5597)
- Malin Pedersen (ORCID: https://orcid.org/0000-0003-1887-733X)
- Thomas Zichner (ORCID: https://orcid.org/0000-0001-9848-7598)
- Ulrich Reiser
- Alan A. Melcher (ORCID: https://orcid.org/0000-0002-2042-3380)
- Kevin Joseph Harrington (ORCID: https://orcid.org/0000-0002-6014-348X)
- Sebastian Carotta (ORCID: https://orcid.org/0009-0009-1156-5254)
- Jehanne Hassan (ORCID: https://orcid.org/0000-0003-3353-6605)
- Philippe Slos
- Christian Mandl (ORCID: https://orcid.org/0009-0005-0065-6792)
- Anton Patrikeev (ORCID: https://orcid.org/0009-0000-0638-8390)
- Louise Giffin
- Mary Murphy
- Lingqi Luo
- Anne Vogt
- Rachel Hunt
- Paolo Chetta
- Masahiro Ono
- Reniqua House
Institutions
- Royal Marsden NHS Foundation Trust (GB)
- Boehringer Ingelheim (Germany) (DE)
- Institute of Cancer Research (GB)
- Breast Cancer Now (GB)
- Boehringer Ingelheim (Austria) (AT)
- Royal Marsden Hospital (GB)
- Boehringer Ingelheim (France) (FR)
- Imperial College London (GB)
Publication Details
- Journal
- British Journal of Cancer
- Published
- 2026-10-15
- DOI
- https://doi.org/10.1038/s41416-026-03634-4
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Cancer Research UK