Magnitude of Therapeutic STING Activation Determines CD8+ T Cell-Mediated Anti-tumor Immunity
Open accessAbstract
Intratumoral (IT) STING activation results in tumor regression in preclinical models, yet factors dictating the balance between innate and adaptive anti-tumor immunity are unclear. Here, clinical candidate STING agonist ADU-S100 (S100) is used in an IT dosing regimen optimized for adaptive immunity to uncover requirements for a T cell-driven response compatible with checkpoint inhibitors (CPIs). In contrast to high-dose tumor ablative regimens that result in systemic S100 distribution, low-dose immunogenic regimens induce local activation of tumor-specific CD8 + effector T cells that are responsible for durable anti-tumor immunity and can be enhanced with CPIs. Both hematopoietic cell STING expression and signaling through IFNAR are required for tumor-specific T cell activation, and in the context of optimized T cell responses, TNFα is dispensable for tumor control. In a poorly immunogenic model, S100 combined with CPIs generates a survival benefit and durable protection. These results provide fundamental mechanistic insights into STING-induced anti-tumor immunity.
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Direct activation of the host STING pathway through intratumoral injections of synthetic cyclic dinucleotides is an attractive therapeutic strategy in multiple preclinical cancer models.
“Direct activation of the host STING pathway through intratumoral injections of synthetic cyclic dinucleotides has shown to be an attractive therapeutic strategy in multiple preclinical cancer models22,25,42.”
From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [25]
The available indexed passages contain a table of contents and reference links, but no substantive text about treatment outcomes. Searches for intratumoral synthetic cyclic dinucleotides, multiple tumor models, and tumor regression found no passage that establishes the claimed preclinical therapeutic promise. (LLM, conf=0.72)
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The balance of STING signaling orchestrates immunity in cancer
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Targeting Stimulator of Interferon Genes (STING): A Medicinal Chemistry Perspective
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STING licensing of type I dendritic cells potentiates antitumor immunity
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STING suppresses bone cancer pain via immune and neuronal modulation
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Intratumoral Immunotherapy: From Trial Design to Clinical Practice
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Demystifying the cGAS-STING pathway: precision regulation in the tumor immune microenvironment
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Biochemistry, Cell Biology, and Pathophysiology of the Innate Immune cGAS–cGAMP–STING Pathway
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Significance of the cGAS-STING Pathway in Health and Disease
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Targeting Innate Immunity in Cancer Therapy
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Pharmacological Modulation of the STING Pathway for Cancer Immunotherapy
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Inhibition of the ATM/Chk2 axis promotes cGAS/STING signaling in ARID1A-deficient tumors
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Targeting innate sensing in the tumor microenvironment to improve immunotherapy
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Epigenetic state determines the in vivo efficacy of STING agonist therapy
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Nucleic Acid Sensors as Therapeutic Targets for Human Disease
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Lanthanide-Nucleotide Coordination Nanoparticles for STING Activation
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- Authors
- Sivick, K. E., Desbien, A. L., Glickman, L. H., Reiner, G. L., Corrales, L., Surh, N. H., Hudson, T. E., Vu, U. T., Francica, B. J., Banda, T., Katibah, G. E., Kanne, D. B., Leong, J. J., Metchette, K., Bruml, J. R., Ndubaku, C. O., McKenna, J. M., Feng, Y., Zheng, L., Bender, S. L., Cho, C. Y., Leong, M. L., van Elsas, A., Dubensky, T. W., & McWhirter, S. M.
- Affiliations
- Aduro BioTech (United States) (US)
- Genomics Institute of the Novartis Research Foundation (US)
- Corresponding author
- McWhirter, Sarah M.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 25
- Issue
- 11
- Pages
- 3074-3085.e5
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2905027070
- Cited by
- 451
- References
- 42
- Citations by year
- 2026: 55 · 2025: 64 · 2024: 67 · 2023: 65 · 2022: 63 · 2021: 61 · 2020: 50 · 2019: 26
- FWCI
- 12.97
- Type
- journal article
- Language
- en
- Update notices
- erratum (2019-10-15)
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Aduro Biotech, Inc.
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- STING activation, ADU-S100, CD8+ T cells, antitumor immunity, immune checkpoint inhibitors, IFNAR signaling, TNF-α, intratumoral immunotherapy, innate and adaptive immunity
- MeSH terms
- STING Protein, Animals, Dose-Response Relationship, Immunologic, Hematopoiesis, Immunity, Membrane Proteins, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasms, S100 Proteins, Cytokines, CD8-Positive T-Lymphocytes, Drug Resistance, Neoplasm, Cell Line, Tumor, CTLA-4 Antigen, Programmed Cell Death 1 Receptor
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