Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity

Corrales, Leticia; Glickman, Laura Hix; McWhirter, Sarah M.; Kanne, David B.; Sivick, Kelsey E.; Katibah, George E.; Woo, Seng-Ryong; Lemmens, Edward; Banda, Tamara; Leong, Justin J.; Metchette, Ken; Dubensky, Thomas W.; Gajewski, Thomas F.

doi:10.1016/j.celrep.2015.04.031

Cited by 1,560interferon and immune responsesImmunotherapy and Immune ResponsesCancer Immunotherapy and Biomarkers

Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity

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Corrales, Leticia, Glickman, Laura Hix, McWhirter, Sarah M., Kanne, David B., Sivick, Kelsey E., Katibah, George E., Woo, Seng-Ryong, Lemmens, Edward +5 more·2015·Cell Reports

DOI 10.1016/j.celrep.2015.04.031PMC PMC4440852

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Abstract

Spontaneous tumor-initiated T cell priming is dependent on IFN-β production by tumor-resident dendritic cells. On the basis of recent observations indicating that IFN-β expression was dependent upon activation of the host STING pathway, we hypothesized that direct engagement of STING through intratumoral (IT) administration of specific agonists would result in effective anti-tumor therapy. After proof-of-principle studies using the mouse STING agonist DMXAA showed a potent therapeutic effect, we generated synthetic cyclic dinucleotide (CDN) derivatives that activated all human STING alleles as well as murine STING. IT injection of STING agonists induced profound regression of established tumors in mice and generated substantial systemic immune responses capable of rejecting distant metastases and providing long-lived immunologic memory. Synthetic CDNs have high translational potential as a cancer therapeutic.

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In host dendritic cells, STING-mediated IFN-β induction is essential for their activation and the cross-priming of cytotoxic T cells.
“In host dendritic cells, STING-mediated IFN-β induction has been well characterized and shown to be essential for their activation and the cross-priming of cytotoxic T cells22,23.”
From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [22]
The Results report STING-dependent IFN-β production and activation markers in dendritic cells, while the Introduction describes type I IFN signaling as critical for tumor-specific T-cell priming and dendritic-cell cross-presentation. However, the paper does not establish that IFN-β induction itself is essential for dendritic-cell activation or cross-priming; those are more specific causal claims than the cited passages support. Page numbers are not available in our copy. (LLM, conf=0.84)
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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 [22]
Natural and artificially synthetic cyclic dinucleotides have been developed as STING agonists for cancer immunotherapy.
“Sharing similar structures and biological characteristics with cGAMP, some natural and artificially synthetic cyclic dinucleotides (CDNs) are developed as STING agonists for cancer immunotherapy [265–267].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [267]

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Sauer JD Sotelo-Troha K von Moltke J Monroe KM Rae CS Brubaker SW Hyodo M Hayakawa Y Woodward JJ Portnoy DA 2011 The N-ethyl-N-nitrosourea-induced Goldenticket mouse mutant reveals an essential function of Sting in the in vivo interferon response to Listeria monocytogenes and cyclic dinucleotides Infection and immunity 79 688 694 21098106 PMC3028833

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Authors: Corrales, L., Glickman, L. H., McWhirter, S. M., Kanne, D. B., Sivick, K. E., Katibah, G. E., Woo, S.-R., Lemmens, E., Banda, T., Leong, J. J., Metchette, K., Dubensky, T. W., & Gajewski, T. F.
Affiliations: University of Chicago (US)
Aduro BioTech (United States) (US)
Corresponding author: Dubensky, Thomas W.
Gajewski, Thomas F.
ORCID: Corrales, Leticia
McWhirter, Sarah M.
Sivick, Kelsey E.
Woo, Seng-Ryong
Lemmens, Edward
Dubensky, Thomas W.
Gajewski, Thomas F.
Venue: Cell Reports
Publisher: Elsevier BV
Published: 2015-05
Volume: 11
Issue: 7
Pages: 1018-1030
ISSN: 2211-1247 (ISSN-L)
DOI: 10.1016/j.celrep.2015.04.031
PMC: PMC4440852
OpenAlex: W1898887656
Cited by: 1,560
References: 55
Citations by year: 2026: 153 · 2025: 169 · 2024: 187 · 2023: 196 · 2022: 153 · 2021: 183 · 2020: 139 · 2019: 133 · 2018: 96 · 2017: 92 · 2016: 42 · 2015: 17
FWCI: 40.60
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Cell Reports (publishedVersion, cc-by)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: University of California Berkeley
National Cancer Institute (P01CA97296, R01CA181160, P01CA097296, P30CA014599)
Topics: Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords: STING activation, tumor microenvironment, intratumoral administration, DMXAA, interferon-beta, dendritic cells, T cell priming, antitumor immunity, immunological memory, cancer immunotherapy
MeSH terms: STING Protein, Animals, Antineoplastic Agents, Enzyme-Linked Immunosorbent Assay, Humans, Macrophages, Membrane Proteins, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasms, Experimental, Nucleotides, Cyclic, Transfection, Blotting, Western, Polymerase Chain Reaction, Xanthones, Cell Line, Tumor, Mice, Gene Knockout Techniques, Tumor Microenvironment

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Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity

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