TREX1 limits anti-tumor immunity by degrading short cytosolic DNA molecules
Abstract
TREX1 has recently emerged as a promising therapeutic target in cancer owing to its role in degrading cytosolic DNA and suppressing type I interferon signaling. However, the nature of the immunostimulatory DNA species degraded by TREX1 remains elusive. Here, we show that TREX1 deficiency in murine lung and melanoma tumor cells leads to a substantial, MRE11-dependent increase in short cytosolic DNA fragments that originate preferentially from transcriptionally active regions of the genome, without a corresponding increase in micronuclei. These fragments robustly activate interferon-stimulated genes and drive differentiation of pro-inflammatory macrophages. In syngeneic mice, tumors derived from Trex1-knockout cells exhibit delayed growth, increased sensitivity to anti-PD-1 immune checkpoint blockade, and extended survival. These effects depend on an intact immune system and foster durable anti-tumor memory. Together, our results reveal that short, transcription-derived cytosolic DNA fragments are key TREX1 substrates mediating immune activation in cancer, establishing TREX1 inhibition as a compelling strategy to enhance tumor immunogenicity.
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BibTeX
@article{yang2026trex1,
title = {{TREX1 limits anti-tumor immunity by degrading short cytosolic DNA molecules}},
author = {Chun-Yen Yang and Bayan Chami and Chiara Ursino and Silpa Mary Johnson and Julien Faget and Clément Mettling and Laurent Gros and Philippe Pasero and Yea-Lih Lin},
journal = {EMBO Reports},
year = {2026},
month = oct,
doi = {10.1038/s44319-026-00961-8},
url = {https://hal.science/hal-05804257v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - TREX1 limits anti-tumor immunity by degrading short cytosolic DNA molecules
AU - Chun-Yen Yang
AU - Bayan Chami
AU - Chiara Ursino
AU - Silpa Mary Johnson
AU - Julien Faget
AU - Clément Mettling
AU - Laurent Gros
AU - Philippe Pasero
AU - Yea-Lih Lin
PY - 2026
DA - 2026/10/15
JO - EMBO Reports
DO - 10.1038/s44319-026-00961-8
UR - https://hal.science/hal-05804257v1
AB - TREX1 has recently emerged as a promising therapeutic target in cancer owing to its role in degrading cytosolic DNA and suppressing type I interferon signaling. However, the nature of the immunostimulatory DNA species degraded by TREX1 remains elusive. Here, we show that TREX1 deficiency in murine lung and melanoma tumor cells leads to a substantial, MRE11-dependent increase in short cytosolic DNA fragments that originate preferentially from transcriptionally active regions of the genome, without a corresponding increase in micronuclei. These fragments robustly activate interferon-stimulated genes and drive differentiation of pro-inflammatory macrophages. In syngeneic mice, tumors derived from Trex1-knockout cells exhibit delayed growth, increased sensitivity to anti-PD-1 immune checkpoint blockade, and extended survival. These effects depend on an intact immune system and foster durable anti-tumor memory. Together, our results reveal that short, transcription-derived cytosolic DNA fragments are key TREX1 substrates mediating immune activation in cancer, establishing TREX1 inhibition as a compelling strategy to enhance tumor immunogenicity.
SN - 1469-221X
SN - 1469-3178
ER -