Related Experiment Video

Updated: Jan 13, 2026

Stimulation of Cytoplasmic DNA Sensing Pathways In Vitro and In Vivo
11:44

Stimulation of Cytoplasmic DNA Sensing Pathways In Vitro and In Vivo

Published on: September 18, 2014

9.3K

Ubiquitination-directed cytosolic DNA degradation governs cGAS-STING-mediated immune response to DNA damage

Lei Li1, Qi Ye1, Jinlu Ma2

  • 1Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P.R. China.

Cancer Cell
|January 9, 2026
PubMed

Insights

DNA damage triggers immune responses via cGAS-STING signaling, but cancer can block this. We found that USP7 regulates TREX1, controlling DNA breakdown and immune activation, offering new targets for cancer immunotherapy.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cancer Research

Background:

  • cGAS-STING pathway activation in cancer relies on cytosolic DNA from DNA damage.
  • Clinical applications of cGAS-STING pathway for immunotherapy have shown limited success.
  • Understanding the link between DNA damage and immunotherapy is crucial.

Purpose of the Study:

  • To investigate the role of ubiquitination in cytosolic DNA degradation and its impact on cGAS-STING activation.
  • To elucidate the mechanism by which TREX1 levels are regulated and influence immune responses.
  • To identify potential therapeutic targets for enhancing radioimmunotherapy.

Main Methods:

  • Investigated the interplay between E3 ubiquitin ligase SPOP, deubiquitinase USP7, and cytosolic DNA exonuclease TREX1.
  • Assessed the impact of SPOP mutations and USP7 overexpression on TREX1 levels and DNA degradation.
  • Analyzed the correlation between USP7 expression, tumor-infiltrating lymphocytes, and disease progression in cancer patients.
  • Evaluated the efficacy of USP7 inhibitors in restoring immune responses following radiation treatment.

Main Results:

  • Ubiquitination-directed degradation of TREX1 is critical for cGAS-STING activation after DNA damage.
  • SPOP mutations or USP7 overexpression lead to increased TREX1, promoting DNA degradation and suppressing immune activation.
  • Elevated USP7 expression in patients correlates with fewer tumor-infiltrating lymphocytes and worse outcomes with chemoradiotherapy.
  • USP7 inhibitors decrease TREX1 levels and enhance immune responses to radiation.

Conclusions:

  • The study reveals a novel mechanism linking DNA damage, TREX1 regulation, and immune activation through ubiquitination.
  • USP7 plays a key role in controlling cytosolic DNA levels and modulating anti-tumor immunity.
  • USP7 inhibitors represent a promising strategy to improve the efficacy of radioimmunotherapy by restoring cGAS-STING pathway function.
Keywords:
SPOP mutationTREX1cytosolic DNAimmune responsesradiotherapy

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