TREX1 limits anti-tumor immunity by degrading short cytosolic DNA molecules.

TREX1 deficiency in murine lung and melanoma tumor cells causes a substantial, MRE11-dependent increase in short cytosolic DNA fragments from transcriptionally active regions.

• Why it matters: Understanding the specific DNA species degraded by TREX1 is crucial because their accumulation activates immune responses and influences tumor growth and therapy response.
• What they did: The study used murine tumor cells with TREX1 deficiency, revealing increased short cytosolic DNA fragments originating from active genomic regions, which activate interferon-stimulated genes and promote pro-inflammatory macrophage differentiation.
• The result: Tumors from Trex1-knockout cells showed delayed growth, heightened sensitivity to anti-PD-1 therapy, and longer survival in mice, suggesting TREX1 inhibition could boost tumor immunogenicity and anti-tumor immunity.