TREX1, also known as three-prime repair exonuclease 1, is a major 3'-5' DNA exonuclease. Its essential function is to digest cytosolic DNA, thereby preventing inappropriate activation of the innate immune system. It is closely associated with the cGAS/STING-Interferon (IFN) signaling pathway, which is crucial for antiviral defense and tumor immunity [2,3,5,6].

In cancer, TREX1 inactivation unleashes STING-IFN signaling. In multiple mouse tumor models, TREX1-deficient cancer cells recruit T and natural killer (NK) cells, are sensitized to NK cell-derived IFNγ, and cooperate with programmed cell death protein 1 blockade to enhance immunogenicity [1]. In radiotherapy-related studies, radiation doses above 12-18 Gy induce TREX1 in cancer cells, which then degrades cytosolic DNA, attenuating immunogenicity. Repeated irradiation at non-TREX1-inducing doses amplifies interferon-β production, leading to immune cell recruitment and activation [4]. In the context of autoimmunity, Trex1-deficient mice develop lethal autoimmunity, with single-stranded DNA from endogenous retroelements accumulating in Trex1-deficient cells [3].

In conclusion, TREX1 is a key regulator in maintaining immune homeostasis. Its function in degrading cytosolic DNA is vital for preventing autoimmunity. In cancer, targeting TREX1 shows potential as a strategy to enhance antitumor immunity, as demonstrated by mouse models. These findings provide important insights into the role of TREX1 in autoimmunity and cancer, offering potential therapeutic directions.

References:

1. Tani, Tetsuo, Mathsyaraja, Haritha, Campisi, Marco, Cain, Jennifer, Barbie, David A. . TREX1 Inactivation Unleashes Cancer Cell STING-Interferon Signaling and Promotes Antitumor Immunity. In Cancer discovery, 14, 752-765. doi:10.1158/2159-8290.CD-23-0700. https://pubmed.ncbi.nlm.nih.gov/38227896/

2. Wang, Qing, Du, Juan, Hua, Shucheng, Zhao, Ke. 2022. TREX1 plays multiple roles in human diseases. In Cellular immunology, 375, 104527. doi:10.1016/j.cellimm.2022.104527. https://pubmed.ncbi.nlm.nih.gov/35468328/

3. Stetson, Daniel B, Ko, Joan S, Heidmann, Thierry, Medzhitov, Ruslan. . Trex1 prevents cell-intrinsic initiation of autoimmunity. In Cell, 134, 587-98. doi:10.1016/j.cell.2008.06.032. https://pubmed.ncbi.nlm.nih.gov/18724932/

4. Vanpouille-Box, Claire, Alard, Amandine, Aryankalayil, Molykutty J, Formenti, Silvia C, Demaria, Sandra. 2017. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. In Nature communications, 8, 15618. doi:10.1038/ncomms15618. https://pubmed.ncbi.nlm.nih.gov/28598415/

5. Tao, Sha-Sha, Wu, Guo-Cui, Zhang, Qin, Pan, Hai-Feng, Ye, Dong-Qing. . TREX1 As a Potential Therapeutic Target for Autoimmune and Inflammatory Diseases. In Current pharmaceutical design, 25, 3239-3247. doi:10.2174/1381612825666190902113218. https://pubmed.ncbi.nlm.nih.gov/31475890/

6. Lim, Junghyun, Rodriguez, Ryan, Williams, Katherine, Qu, Yan, Heger, Klaus. . The Exonuclease TREX1 Constitutes an Innate Immune Checkpoint Limiting cGAS/STING-Mediated Antitumor Immunity. In Cancer immunology research, 12, 663-672. doi:10.1158/2326-6066.CIR-23-1078. https://pubmed.ncbi.nlm.nih.gov/38489753/