Agonist-Mediated Activation of STING Induces Apoptosis in Malignant B Cells

Cancer Res. 2016 Apr 15;76(8):2137-52. doi: 10.1158/0008-5472.CAN-15-1885. Epub 2016 Mar 7.


Endoplasmic reticulum (ER) stress responses through the IRE-1/XBP-1 pathway are required for the function of STING (TMEM173), an ER-resident transmembrane protein critical for cytoplasmic DNA sensing, IFN production, and cancer control. Here we show that the IRE-1/XBP-1 pathway functions downstream of STING and that STING agonists selectively trigger mitochondria-mediated apoptosis in normal and malignant B cells. Upon stimulation, STING was degraded less efficiently in B cells, implying that prolonged activation of STING can lead to apoptosis. Transient activation of the IRE-1/XBP-1 pathway partially protected agonist-stimulated malignant B cells from undergoing apoptosis. In Eμ-TCL1 mice with chronic lymphocytic leukemia, injection of the STING agonist 3'3'-cGAMP induced apoptosis and tumor regression. Similarly efficacious effects were elicited by 3'3'-cGAMP injection in syngeneic or immunodeficient mice grafted with multiple myeloma. Thus, in addition to their established ability to boost antitumoral immune responses, STING agonists can also directly eradicate malignant B cells. Cancer Res; 76(8); 2137-52. ©2016 AACR.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • B-Lymphocytes / cytology
  • B-Lymphocytes / metabolism*
  • Cell Line
  • Cyclic GMP / administration & dosage
  • Cyclic GMP / pharmacology
  • Injections, Intraperitoneal
  • Membrane Proteins / agonists*
  • Membrane Proteins / physiology
  • Mice


  • Membrane Proteins
  • Sting1 protein, mouse
  • Cyclic GMP