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

Area of Science:

• Immunology
• Cancer Biology
• Molecular Biology

Background:

• The NF-κB pathway is critical for tumor growth and radioresistance.
• Its role in radiation-induced anti-tumor immunity is not fully understood.

Purpose of the Study:

• To investigate the distinct roles of canonical and non-canonical NF-κB pathways in radiation therapy.
• To explore the potential of targeting NF-κB for improved cancer treatment.

Main Methods:

• Utilized murine models to study the effects of NF-κB pathway modulation on radiation therapy outcomes.
• Investigated the STING sensor-dependent DNA-sensing pathway and its interaction with NF-κB signaling in dendritic cells.
• Assessed type I Interferon (IFN) expression and RelA recruitment to the Ifnb promoter.

Main Results:

• Inhibition of the canonical NF-κB pathway reduced the efficacy of ionizing radiation (IR).
• Deficiency in the non-canonical NF-κB pathway enhanced IR-induced anti-tumor immunity.
• Non-canonical NF-κB signaling in dendritic cells, activated via STING, suppresses type I IFN production.
• A specific non-canonical NF-κB inhibitor improved the anti-tumor effects of IR in preclinical models.

Conclusions:

• Canonical and non-canonical NF-κB pathways have opposing roles in radiation-induced anti-tumor immunity.
• Targeting the non-canonical NF-κB pathway presents a promising strategy to enhance cancer radiotherapy efficacy.