Systemic inactivation of TREX1 induces selective inflammation of the tumor microenvironment and invigorated T-cell-mediated tumor control
Therapeutic innate immune-stimulation within the tumor microenvironment can potentiate endogenous antitumor T-cell immunity. Strategies for controlled activation of cGAS/STING signaling are currently under intense investigation. DNase 3′-repair exonuclease 1 (TREX1) is essential for cellular DNA dis...
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| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
1 August 2025
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| In: |
Cancer research
Year: 2025, Volume: 85, Issue: 15, Pages: 2876-2889 |
| ISSN: | 1538-7445 |
| DOI: | 10.1158/0008-5472.CAN-24-2262 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1158/0008-5472.CAN-24-2262
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| Author Notes: | Emilija Marinkovic, Minyi Chen, Nadja Schubert, Elif Dogan Dar, Tanja Poth, Janet Y. Leung, Jack Lohre, Jennifer M. Sahni, Christine Tun, Pavithra Rajeswaran, Tanja Mehlo-Jensen, Olivia Perng, C. Mark Hill, Pallavur Sivakumar, Michael J. Barnes, Rohit Malik, Rayk Behrendt, and Axel Roers |
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| 520 | |a Therapeutic innate immune-stimulation within the tumor microenvironment can potentiate endogenous antitumor T-cell immunity. Strategies for controlled activation of cGAS/STING signaling are currently under intense investigation. DNase 3′-repair exonuclease 1 (TREX1) is essential for cellular DNA disposal, which prevents autoimmunity ensuing from cGAS/STING activation by endogenous DNA. TREX1-deficient tumor cells elicit enhanced protective immunity in syngeneic models. In this study, we showed that induced inactivation of the Trex1 gene in host (noncancer) cells yields improved type I IFN- and T-cell–dependent control of established TREX1-competent tumors. Host TREX1 deficiency was well tolerated and triggered selective immune cell infiltration into tumors but not into other tissues. Induced systemic loss of TREX1 in tumor-bearing mice resulted in enhanced intratumoral T-cell proliferation and massive increase in numbers of effector and effector-like “exhausted” cells, enabling complete rejection in combination with checkpoint inhibition. To conclude, systemic TREX1 inhibition is a promising approach to boost antitumor immunity and to overcome immune evasion mediated by cancer cell–intrinsic cGAS/STING inactivation. | ||
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