Non-canonical NF-κB Antagonizes STING Sensor-Mediated DNA Sensing in Radiotherapy

Immunity. 2018 Sep 18;49(3):490-503.e4. doi: 10.1016/j.immuni.2018.07.008. Epub 2018 Aug 28.


The NF-κB pathway plays a crucial role in supporting tumor initiation, progression, and radioresistance of tumor cells. However, the role of the NF-κB pathway in radiation-induced anti-tumor host immunity remains unclear. Here we demonstrated that inhibiting the canonical NF-κB pathway dampened the therapeutic effect of ionizing radiation (IR), whereas non-canonical NF-κB deficiency promoted IR-induced anti-tumor immunity. Mechanistic studies revealed that non-canonical NF-κB signaling in dendritic cells (DCs) was activated by the STING sensor-dependent DNA-sensing pathway. By suppressing recruitment of the transcription factor RelA onto the Ifnb promoter, activation of the non-canonical NF-κB pathway resulted in decreased type I IFN expression. Administration of a specific inhibitor of the non-canonical NF-κB pathway enhanced the anti-tumor effect of IR in murine models. These findings reveal the potentially interactive roles for canonical and non-canonical NF-κB pathways in IR-induced STING-IFN production and provide an alternative strategy to improve cancer radiotherapy.

Keywords: DNA sensing; STING; dendritic cells; non-canonical NF-κB; radiotherapy; type I IFNs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Colonic Neoplasms / immunology
  • Colonic Neoplasms / radiotherapy*
  • DNA / immunology
  • Dendritic Cells / immunology*
  • Disease Models, Animal
  • Humans
  • Immunity, Cellular
  • Melanoma / immunology
  • Melanoma / radiotherapy*
  • Melanoma, Experimental
  • Membrane Proteins / metabolism
  • Mice
  • NF-kappa B / metabolism*
  • Neoplasms, Experimental / immunology
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / radiotherapy*
  • Radiation Tolerance
  • Radiation, Ionizing
  • Radiotherapy / methods*
  • Receptors, Pattern Recognition / metabolism*
  • Signal Transduction
  • Transcription Factor RelA / metabolism
  • Xenograft Model Antitumor Assays


  • Membrane Proteins
  • NF-kappa B
  • Receptors, Pattern Recognition
  • Sting1 protein, mouse
  • Transcription Factor RelA
  • DNA