Augmenting interferon-β and anti-PD-L1 antibody bolsters non-ablative radiotherapy to leverage potent abscopal effect in metastatic cancers.

Background: The abscopal effect is a systemic anti-tumor immune response induced by local radiotherapy (RT), resulting in regression of distant, non-irradiated tumors. Although ablative RT is more effective than conventionally fractionated RT in inducing this response, the underlying mechanisms remain incompletely understood, and strategies to enhance the abscopal effect following conventional RT are still needed. Methods: We compared the immunological and therapeutic effects of ablative RT (15 Gy in a single fraction) and non-ablative RT (4 Gy in 10 fractions; biologically equivalent to 40 Gy) using murine breast cancer models. Tumor growth, immune cell infiltration, dendritic cell activation, cytokine expression and type I interferon signaling were analyzed. Functional studies were performed using CD8 Results: Ablative radiation induced abscopal response characterized by significant suppression of distant tumor growth, whereas non-ablative RT failed to elicit this effect despite comparable local tumor control. The abscopal response depended on CD8 Conclusions: Our findings identify IFN-β as a critical mediator of RT-induced abscopal immunity and demonstrate that IFN-β supplementation can overcome the limited systemic efficacy of conventional fractionated RT. These results provide a rationale for combining IFN-β with radiotherapy and immune checkpoint blockade to enhance systemic anti-tumor immunity.