Deregulation of STING Signaling in Colorectal Carcinoma Constrains DNA Damage Responses and Correlates With Tumorigenesis

• STING-dependent signaling is frequently suppressed in a variety of cancers
• Inhibition of STING signaling commonly involves silencing of the synthase cGAS
• DNA-damage-induced cytokine production is lost in STING-defective tumors
• Loss of STING function predicts the outcome of DNA-virus-mediated oncolytic activity

SummaryStimulator of interferon genes (STING) has been shown to be critical for controlling antiviral responses as well as anti-tumor adaptive immunity, but little is known regarding its regulation in human tumors. Here, we report that STING signaling is recurrently suppressed in a wide variety of cancers, including colorectal carcinoma. Loss of STING signaling impeded DNA damage responses accountable for generating key cytokines that facilitate tissue repair and anti-tumor T cell priming, such as type I interferons (IFNs). Correspondingly, defective STING function was also highly predictive of effectual DNA-virus-mediated oncolytic activity. Thus, impaired STING responses may enable damaged cells to evade host immunosurveillance processes, although they provide a critical prognostic measurement that could help predict the outcome of effective oncoviral therapy.

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