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Targeting Innate Immune Checkpoint TREX1 Is a Safe and Effective Immunotherapeutic Strategy in Cancer.
Cong Xing1, Xintao Tu1, Wanwan Huai1
1Department of Immunology, UT Southwestern Medical Center, Dallas, Texas.
Targeting Three-prime repair exonuclease 1 (TREX1) with small molecules or knockout cells enhances antitumor immunity. TREX1 inhibition suppresses tumors and boosts immune responses, offering new cancer immunotherapy strategies.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Three-prime repair exonuclease 1 (TREX1) degrades cytosolic DNA, preventing cGAS-STING pathway activation.
- Cancer cells upregulate TREX1 under genotoxic stress, evading type I interferon (IFN-I) antitumor immunity.
- Targeting TREX1 presents a strategy to enhance antitumor immunity and therapeutic outcomes.
Purpose of the Study:
- To identify small-molecule inhibitors (SMIs) of TREX1.
- To evaluate the therapeutic potential of TREX1 inhibition in cancer models.
- To explore TREX1 knockout cancer cells as an autologous cancer vaccine.
Main Methods:
- High-throughput screening of TREX1 small-molecule inhibitors (SMIs).
- Assessing compound 296 efficacy in cell-free assays, cancer cell lines, and mouse models.
- Generating and analyzing Trex1 knockout cancer cells and inducible whole-body Trex1 knockout mice.
Main Results:
- Compound 296 selectively inhibited TREX1, induced IFN-I signaling, and suppressed tumor growth in mice.
- TREX1 inhibition stimulated T cell infiltration and synergized with immune checkpoint blockade.
- Trex1 knockout cancer cells acted as autologous vaccines, providing protection against tumor challenge and metastasis.
- Sustained TREX1 loss demonstrated broad antitumor activity and immune safety in adult mice.
Conclusions:
- TREX1 inhibition via SMIs or knockout strategies shows significant antitumor efficacy.
- TREX1 targeting can enhance innate and adaptive immune responses against cancer.
- TREX1-targeted therapies, including SMIs and cancer vaccines, offer promising avenues for cancer immunotherapy.

