The Exonuclease TREX1 Constitutes an Innate Immune Checkpoint Limiting cGAS/STING-Mediated Antitumor Immunity.

Area of Science:

• Immunology
• Molecular Biology
• Cancer Research

Background:

• The DNA exonuclease three-prime repair exonuclease 1 (TREX1) degrades cytosolic DNA, preventing autoimmune responses via the cGAS/STING pathway and type I interferons (IFNs).
• Tumor cells often accumulate cytosolic DNA, potentially triggering immune responses.

Purpose of the Study:

• To investigate the role of TREX1 in limiting tumor immunogenicity and its potential as a therapeutic target.

Main Methods:

• Assessed TREX1's effect on the cGAS/STING pathway in tumor cells.
• Evaluated the impact of TREX1 deficiency on tumor growth in mouse models.
• Analyzed immune cell activation, T-cell exhaustion, and myeloid compartment changes in TREX1-deficient tumors.
• Investigated the combination of TREX1 inhibition with immune checkpoint blockade.

Main Results:

• TREX1 deficiency in tumor cells restricts cGAS/STING activation and type I IFN responses, thereby limiting tumor growth in mice.
• Reduced tumor growth in TREX1-deficient mice required a functional immune system, systemic type I IFN signaling, and tumor cGAS.
• TREX1 loss promoted CD8+ T cell and NK cell activation, reduced T-cell exhaustion, and shifted the myeloid compartment towards an anti-tumor phenotype.
• Combining TREX1 inhibition with T-cell-directed immune checkpoint blockade showed synergistic effects.

Conclusions:

• TREX1 acts as a critical checkpoint limiting tumor immunogenicity by suppressing innate immune pathways.
• Targeting TREX1 can remodel the tumor microenvironment, enhance endogenous antitumor immunity, and synergize with existing immunotherapies.