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Stimulation of Cytoplasmic DNA Sensing Pathways In Vitro and In Vivo
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STING enhances cell death through regulation of reactive oxygen species and DNA damage

Thomas J Hayman1, Marta Baro1, Tyler MacNeil2

  • 1Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA.

Nature Communications
|April 20, 2021
PubMed

Insights

Stimulator of interferon genes (STING) regulates tumor cell survival by controlling reactive oxygen species (ROS) generation. Activating STING may enhance cancer treatment efficacy against DNA-damaging agents.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Treatment resistance to DNA-damaging agents is a major challenge in oncology.
  • Unrecognized regulators of tumor cell survival contribute to treatment failure.

Purpose of the Study:

  • To identify novel regulators of tumor cell survival under DNA-damaging conditions.
  • To investigate the role of STING in regulating cellular responses to ionizing radiation.

Main Methods:

  • Whole-genome CRISPR-Cas9 screening with ionizing radiation as selective pressure.
  • Analysis of STING's role in reactive oxygen species (ROS) homeostasis.
  • Correlation of STING expression with patient outcomes in head and neck squamous cell carcinoma.

Main Results:

  • STING (stimulator of interferon genes) was identified as a key regulator of tumor cell survival.
  • STING loss reduces DNA damage and confers resistance to ionizing radiation by altering ROS homeostasis.
  • Low STING expression in head and neck squamous cell carcinoma correlates with poorer patient outcomes.

Conclusions:

  • STING regulates a transcriptional program controlling ROS generation, impacting DNA damage and therapeutic resistance.
  • Pharmacologic activation of STING potentiates the efficacy of ionizing radiation, suggesting combination therapy potential.
  • STING acts as a crucial regulator of cellular ROS homeostasis and tumor cell sensitivity to DNA-damaging agents.

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