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Peer-reviewedCC BY 4.0Frontiers in Immunology

Context-dependent cGAS–STING signaling in inflammatory bowel disease: cell specificity, lesion state, and therapeutic windows

  • Huihui Bian1,2
  • Wenjing Jin1,2
  • Yuhong Chen1,2
  • Li Su1,2
  • Rongsheng Zhang3
  1. 1Institute of Translational Medicine, Shanghai University
  2. 2School of Medicine, Shanghai University
  3. 3Department of Hepatobiliary Surgery, The Affiliated Wuxi People’s Hospital of Nanjing Medical University
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Abstract

Whether cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling should be inhibited in inflammatory bowel disease (IBD) cannot be answered from pathway abundance alone. Canonical ER–Golgi–TBK1–IRF3/NF-κB signaling can amplify intestinal inflammation, whereas nuclear STING–AHR signaling, T-cell-intrinsic STING, ILC3 sensing, and epithelial antimicrobial programs may support microbial tolerance, host defense, or repair. We therefore examine STING output across subcellular location, signal source and duration, responding cell type, lesion state, and strength of evidence. The most consistent pathogenic evidence comes from experimental colitis with sustained DNA exposure and myeloid or epithelial stress; direct human evidence is more limited, mainly cross-sectional, and heterogeneous between ulcerative colitis and Crohn’s disease. This distinction limits inferences from increased cGAS/STING expression or interferon-stimulated genes, which do not establish cGAMP production, STING trafficking or phosphorylation, TBK1–IRF3 activation, or a causal biological outcome. The available data support a working model rather than a validated temporal sequence: protective and pathogenic programs can coexist within the same lesion, and broad systemic inhibition may impair antimicrobial defense, tolerance, mucosal repair, or tumor immune surveillance. Translation will therefore require cell-resolved target-engagement biomarkers and locally delivered, time-limited interventions tested in longitudinal human tissue and models that preserve microbiota and lesion heterogeneity.

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Cite

BibTeXRIS
BibTeX
@article{bian2026contextdependent,
  title = {{Context-dependent cGAS–STING signaling in inflammatory bowel disease: cell specificity, lesion state, and therapeutic windows}},
  author = {Huihui Bian and Wenjing Jin and Yuhong Chen and Li Su and Rongsheng Zhang},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1970206},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1970206/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Context-dependent cGAS–STING signaling in inflammatory bowel disease: cell specificity, lesion state, and therapeutic windows
AU  - Huihui Bian
AU  - Wenjing Jin
AU  - Yuhong Chen
AU  - Li Su
AU  - Rongsheng Zhang
PY  - 2026
DA  - 2026/10/20
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1970206
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1970206/full
AB  - Whether cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling should be inhibited in inflammatory bowel disease (IBD) cannot be answered from pathway abundance alone. Canonical ER–Golgi–TBK1–IRF3/NF-κB signaling can amplify intestinal inflammation, whereas nuclear STING–AHR signaling, T-cell-intrinsic STING, ILC3 sensing, and epithelial antimicrobial programs may support microbial tolerance, host defense, or repair. We therefore examine STING output across subcellular location, signal source and duration, responding cell type, lesion state, and strength of evidence. The most consistent pathogenic evidence comes from experimental colitis with sustained DNA exposure and myeloid or epithelial stress; direct human evidence is more limited, mainly cross-sectional, and heterogeneous between ulcerative colitis and Crohn’s disease. This distinction limits inferences from increased cGAS/STING expression or interferon-stimulated genes, which do not establish cGAMP production, STING trafficking or phosphorylation, TBK1–IRF3 activation, or a causal biological outcome. The available data support a working model rather than a validated temporal sequence: protective and pathogenic programs can coexist within the same lesion, and broad systemic inhibition may impair antimicrobial defense, tolerance, mucosal repair, or tumor immune surveillance. Translation will therefore require cell-resolved target-engagement biomarkers and locally delivered, time-limited interventions tested in longitudinal human tissue and models that preserve microbiota and lesion heterogeneity.
SN  - 1664-3224
ER  -