STING enhances cell death through regulation of reactive oxygen species and DNA damage

Thomas J. Hayman, Marta Baro, Tyler MacNeil, Chatchai Phoomak, Thazin Nwe Aung, Wei Cui, Kevin Leach, Radhakrishnan Iyer, Sreerupa Challa, Teresa Sandoval-Schaefer, Barbara A. Burtness, David L. Rimm and Joseph N. Contessa ()
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Thomas J. Hayman: Yale University School of Medicine
Marta Baro: Yale University School of Medicine
Tyler MacNeil: Yale University School of Medicine
Chatchai Phoomak: Yale University School of Medicine
Thazin Nwe Aung: Yale University School of Medicine
Wei Cui: Yale University School of Medicine
Kevin Leach: F-Star Therapeutics
Radhakrishnan Iyer: F-Star Therapeutics
Sreerupa Challa: F-Star Therapeutics
Teresa Sandoval-Schaefer: Yale University
Barbara A. Burtness: Yale School of Medicine
David L. Rimm: Yale University School of Medicine
Joseph N. Contessa: Yale University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Resistance to DNA-damaging agents is a significant cause of treatment failure and poor outcomes in oncology. To identify unrecognized regulators of cell survival we performed a whole-genome CRISPR-Cas9 screen using treatment with ionizing radiation as a selective pressure, and identified STING (stimulator of interferon genes) as an intrinsic regulator of tumor cell survival. We show that STING regulates a transcriptional program that controls the generation of reactive oxygen species (ROS), and that STING loss alters ROS homeostasis to reduce DNA damage and to cause therapeutic resistance. In agreement with these data, analysis of tumors from head and neck squamous cell carcinoma patient specimens show that low STING expression is associated with worse outcomes. We also demonstrate that pharmacologic activation of STING enhances the effects of ionizing radiation in vivo, providing a rationale for therapeutic combinations of STING agonists and DNA-damaging agents. These results highlight a role for STING that is beyond its canonical function in cyclic dinucleotide and DNA damage sensing, and identify STING as a regulator of cellular ROS homeostasis and tumor cell susceptibility to reactive oxygen dependent, DNA damaging agents.

Date: 2021
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DOI: 10.1038/s41467-021-22572-8

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