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

The NF-kappa B pathway plays a crucial role in supporting tumor initiation, progression, and radioresistance of tumor cells. However, the role of the NF-kappa B pathway in radiation-induced anti-tumor host immunity remains unclear. Here we demonstrated that inhibiting the canonical NF-kappa B pathway dampened the therapeutic effect of ionizing radiation (IR), whereas non-canonical NF-kappa B deficiency promoted IR- induced anti-tumor immunity. Mechanistic studies revealed that non-canonical NF-kappa B 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-kappa B pathway resulted in decreased type I IFN expression. Administration of a specific inhibitor of the non-canonical NF-kappa B pathway enhanced the anti-tumor effect of IR in murine models. These findings reveal the potentially interactive roles for canonical and noncanonical NF-kappa B pathways in IR-induced STING-FN production and provide an alternative strategy to improve cancer radiotherapy.