Intravenous STING Agonist Supercharges Radiotherapy to Trigger Anti-Tumour Immunity

A new generation of immune-activating drugs may finally be ready to unlock the full potential of one of cancer medicine’s oldest weapons. In a comprehensive preclinical study published in the British Journal of Cancer, researchers at The Institute of Cancer Research in London, working with scientists at Boehringer Ingelheim, have shown that a novel, systemically administered STING agonist called BI 1703880 can transform low-dose radiotherapy from a merely cytotoxic treatment into a platform for durable, immune-mediated tumour control. The findings come at a pivotal moment, as first-generation STING agonists delivered directly into tumours have largely disappointed in early clinical trials, shifting attention toward agents that can be given intravenously and reach disease wherever it hides.

The STING pathway, short for stimulator of interferon genes, is the cellular alarm system that senses misplaced DNA. Under normal conditions, the enzyme cGAS detects cytosolic DNA, often released by viruses or damaged cells, and manufactures cyclic dinucleotides that bind to STING, a protein anchored in the endoplasmic reticulum. This binding triggers a conformational change that recruits the kinase TBK1, which in turn phosphorylates the transcription factors IRF3 and NF-kappaB, unleashing a burst of type I interferons and proinflammatory cytokines. In cancer biology, this pathway is doubly important: radiotherapy itself depends on cGAS/STING signalling in immune cells for much of its anti-tumour effect, and dendritic cells, which express high levels of STING, are thought to be the critical translators of tumour cell death into productive T cell immunity.

The London-led team set out to establish whether BI 1703880 could reliably switch this machinery on. Using paired THP-1 reporter cell lines, one carrying functional STING and one knocked out by CRISPR/Cas9, they demonstrated that the compound drives robust phosphorylation of STING, TBK1 and IRF3 only where the target protein is present, confirming strict on-target specificity. The same dose-dependent pathway activation appeared in primary human peripheral blood mononuclear cells from three independent donors. Importantly, because human STING exists in five major genetic variants, the researchers engineered reporter cells expressing each variant and found that the agonist engaged all five, a property that could matter enormously for translating the drug across genetically diverse patient populations.

RNA sequencing deepened the picture. Treated THP-1 cells and human donor-derived dendritic cells showed a clear induction of interferon-related genes, cytokine transcripts and, notably, the HLA-A, HLA-B and HLA-C genes that present antigens to cytotoxic CD8-positive T cells. Bio-Plex assays confirmed corresponding secretion of IFN-alpha, IFN-beta, IFN-lambda, CXCL10, CCL2, CCL5 and TNF-alpha. In short, the compound did exactly what a dendritic-cell-targeted adjuvant should do: it converted these sentinels into a state primed for cross-presentation and T cell priming.

The in vivo work, however, revealed a fundamental dose dilemma. In mice bearing anaplastic thyroid carcinoma, head and neck squamous cell carcinoma and colorectal tumours, a single high intravenous dose of 20 micromoles per kilogram produced plasma cytokine surges ranging from 1,000 to 60,000 picograms per millilitre, accompanied by dramatic haemorrhagic tumour necrosis and rapid shrinkage within 72 hours. The speed and vascular character of that response suggested effects beyond the desired immunology. Low doses of 7 micromoles per kilogram generated far more modest, transient cytokine peaks that returned to baseline in the blood within 24 hours. The team also noted that a mouse model expressing a constitutively active STING mutation suffers lethal hypercytokinemia, a reminder that chronic, excessive interferon signalling is dangerous. Repeated low-dose treatment, by contrast, caused no significant weight loss and was selected as the foundation for combination studies.

Radiotherapy emerged as the natural partner. The investigators deliberately chose a sub-therapeutic regimen of two 8 Gy fractions on consecutive days, sufficient to slow tumours but not to control them, and increased tumour MHC class I and PD-L1 expression. When repeated low-dose STINGa was layered onto this irradiation in mice with TBPt-4C4 or mEER tumours, the combination significantly improved both tumour control and survival compared with either therapy alone, and mice that achieved cure rejected a subsequent tumour rechallenge, evidence of genuine adaptive immune memory. The synergy held in five additional subcutaneous models, including MC38, TC-1, AT84 and two further thyroid cancer lines, and in orthotopic mEER tumours growing in the lip.

Mechanistically, the combination proved strictly immune-dependent. In immunodeficient NSG mice lacking lymphocytes, the benefit of RT/STINGa collapsed, and antibody-mediated depletion of CD8-positive T cells in wild-type mice similarly eroded tumour control. Spectral flow cytometry using the Nr4a3-timer ‘Tocky’ transgenic reporter system, which tracks the temporal dynamics of T cell receptor signalling, revealed that combination therapy expanded a distinct cluster of intratumoural CD8-positive T cells showing persistent cognate antigen signalling. These cells were highly proliferative, expressing Ki67, activated as shown by CD69, and cytotoxic, indicated by granzyme B, but simultaneously displayed elevated PD-1, CD44, TIM3 and ICOS, hallmarks of an activated-but-exhausted phenotype. The tumour microenvironment itself became measurably more inflamed, with interferon signalling transcripts upregulated and the CD8-to-Treg ratio rising favourably.

That exhaustion signature pointed directly toward checkpoint blockade. Bulk RNA sequencing of tumours treated with the double combination confirmed upregulation of the Pdcd1 and Ctla4 axes, and the team therefore added anti-PD-1 and anti-CTLA-4 antibodies to create a quadruple regimen. The results were striking. In the TBPt-4C4 model, quadruple therapy cured five of six mice, compared with one of six receiving RT/STINGa with isotype controls, while in mEER tumours six of six mice achieved cure. Histology two weeks after treatment initiation showed extensive central necrosis, fibrosis and chronic inflammation with scant residual viable tumour, and increased CD8 infiltration together with elevated granzyme and perforin transcripts suggested restored cytotoxic function rather than merely more T cells. In the TKP-4831 model, cures were not achieved but survival was significantly prolonged.

A bilateral flank experiment added an intriguing systemic dimension. When only the right-sided tumour was irradiated while STINGa circulated systemically, the unirradiated left tumours did not shrink more under combination therapy than with STINGa alone, meaning no classic abscopal effect on growth was observed. Yet CD8-positive T cell infiltration into the unirradiated tumours increased following the combination, indicating that irradiation of one site can seed immune activity against distant disease, even if not yet to a therapeutically decisive degree. The authors also emphasised that the STINGa-induced cytokine response in their models appears to originate predominantly from host immune and stromal cells rather than tumour cells, since several of the tested cancer lines lacked detectable STING signalling and did not secrete interferon-beta upon treatment in vitro.

The study’s authors conclude that STING is firmly validated as a therapeutic target in cancer and that radiotherapy deserves recognition as a rational combination partner for systemically delivered agonists. BI 1703880 is already under evaluation in a phase I clinical trial, and the preclinical framework presented here, sub-therapeutic radiation followed by repeated low-dose systemic agonism and rationally selected checkpoint blockade, offers a roadmap for how such trials might be designed. With first-generation intratumoural agents such as MK-1454 and ADU-S100 having fallen short, the prospect of an intravenous drug that activates innate immunity across multiple tumour sites while synergising with standard radiotherapy represents a genuinely encouraging advance, though the ultimate test will lie in whether this carefully orchestrated immunology survives translation into patients.

Subject of Research: Preclinical evaluation of a systemically delivered STING agonist combined with radiotherapy and immune checkpoint blockade for cancer immunotherapy

Article Title: Preclinical efficacy of a systemically-administered, second-generation STING agonist that promotes anti-tumour immunity in combination with radiotherapy

Article References: Pedersen, M., Hubbard, L. C., Foo, S., Patrikeev, A., Rullan, A., Baldock, H., Mandl, C., Chetta, P., Hassan, J., Dean, I., Guppy, N., Slos, P., Hak, C. C. W., Appleton, E., Patin, E. C., Hunt, R., Weir, J., Ono, M., Oost, T., … Harrington, K. J. (2026). Preclinical efficacy of a systemically-administered, second-generation STING agonist that promotes anti-tumour immunity in combination with radiotherapy. British Journal of Cancer. https://doi.org/10.1038/s41416-026-03634-4

Image Credits: AI Generated

DOI: 10.1038/s41416-026-03634-4

Keywords: STING agonist, BI 1703880, cancer immunotherapy, radiotherapy, cGAS-STING pathway, dendritic cells, CD8 T cells, immune checkpoint inhibitors, PD-1, CTLA-4, tumour microenvironment, preclinical study