ArticleCancer immunology research2024
The Exonuclease TREX1 Constitutes an Innate Immune Checkpoint Limiting cGAS/STING-Mediated Antitumor Immunity.
Article in Cancer immunology research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 39 citations in OpenAlex.
- TREX1 limits anti-tumor immunity by degrading short cytosolic DNA molecules.EMBO reports · 2026Article
- Immune response to DNA and RNA: structural insights, molecular mechanisms, and therapeutic targeting.Molecular biomedicine · 2026Review
- Chemotherapeutic induction of cytosolic single-stranded DNA accumulation sensitizes triple-negative breast cancer to immunotherapy.Journal for immunotherapy of cancer · 2026Article
- Zinc-Doped Calcium Phosphate Nanoagonists Amplifies cGAS-STING Signaling for Boosting Pyroptosis-Induced Cancer Immunotherapy.Journal of functional biomaterials · 2026Article
- Loss of the autoimmune risk gene TREX1 reveals a convergence of mechanisms promoting immune tolerance loss and antitumor immunity.Science advances · 2026Article
- Optimizing next-generation CAR-macrophages against solid tumors: challenges and potential strategies.Journal of hematology & oncology · 2026Review
- Targeting inflammatory microenvironments: overcoming therapy resistance and immunosuppression.Molecular cancer · 2026Review
- CDK10 inhibits innate sensing to constrain antitumor immunity.Nature cancer · 2026Article
- Disordered DNA-binding motif forms a modulation site for inhibiting the cancer immunotherapy target TREX1.Nucleic acids research · 2026Article
- Inducing tumor-intrinsic innate immune response to break cancer immunotherapy resistance.Frontiers in medicine · 2026Review
- STING signaling pathway: An oasis in the glioblastoma immune desert.Theranostics · 2026Review
- Testing immune priming failure in laryngeal squamous cell carcinoma: direct evidence, unresolved links, and a compartment-resolved framework.Frontiers in immunology · 2026Review
- Synergistic neoadjuvant radioimmunotherapy in locally advanced rectal cancer: mechanisms of pathologic response and the shift toward organ preservation.Frontiers in immunology · 2026Review
- Smohaze-Upregulated RFWD3 Competes with TRIM24 to Stabilize TREX1 and Reduce Cytosolic dsDNA in Non-Small Cell Lung Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Activation of cGAS-STING signaling in senescent cells promotes the aging process by remodeling the functions of the immune system.Biogerontology · 2025Review
- Bridging innate and adaptive tumor immunity: cGAS-STING pathway activation to potentiate immune checkpoint blockade.Journal of experimental & clinical cancer research : CR · 2025Review
- Breaking barriers: The cGAS-STING pathway as a novel frontier in cancer immunotherapy.Cancer communications (London, England) · 2025Review
- Activation and regulation of cGAS-STING signaling in cancer cells.Molecular cell · 2025Review
- Targeting Innate Immune Checkpoint TREX1 Is a Safe and Effective Immunotherapeutic Strategy in Cancer.Cancer research · 2025Article
- Integrated multi-omics profiling reveals the role of the DNA methylation landscape in shaping biological heterogeneity and clinical behaviour of metastatic melanoma.Journal of experimental & clinical cancer research : CR · 2025Article
Corrections and comments
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Authors and funding
18 authors at 1 institution in 1 country.
Funding
Abstract
The DNA exonuclease three-prime repair exonuclease 1 (TREX1) is critical for preventing autoimmunity in mice and humans by degrading endogenous cytosolic DNA, which otherwise triggers activation of the innate cGAS/STING pathway leading to the production of type I IFNs. As tumor cells are prone to aberrant cytosolic DNA accumulation, we hypothesized that they are critically dependent on TREX1 activity to limit their immunogenicity. Here, we show that in tumor cells, TREX1 restricts spontaneous activation of the cGAS/STING pathway, and the subsequent induction of a type I IFN response. As a result, TREX1 deficiency compromised in vivo tumor growth in mice. This delay in tumor growth depended on a functional immune system, systemic type I IFN signaling, and tumor-intrinsic cGAS expression. Mechanistically, we show that tumor TREX1 loss drove activation of CD8+ T cells and NK cells, prevented CD8+ T-cell exhaustion, and remodeled an immunosuppressive myeloid compartment. Consequently, TREX1 deficiency combined with T-cell-directed immune checkpoint blockade. Collectively, we conclude that TREX1 is essential to limit tumor immunogenicity, and that targeting this innate immune checkpoint remodels the tumor microenvironment and enhances antitumor immunity by itself and in combination with T-cell-targeted therapies. See related article by Toufektchan et al., p. 673.
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