mtDNA/RNA boosts radiation-induced abscopal effect via M1 macrophage polarization-promoted IFN-β-dependent...

The radiation-induced abscopal effect (RIAE) can suppress distal metastatic lesions and elicit a systemic anti-tumor response; however, the underlying mechanisms remain to be fully elucidated. Current research has shown that autophagy promotes the production of IFN-β by regulating mitochondrial DNA (mtDNA), thereby contributing to the modulation of RIAE. Nevertheless, the downstream pathways through which IFN-β influences RIAE require further investigation. In this study, we observed accumulation of an abundance of mtDNA in the cytosol of mammary tumor cells following RT, along with the presence of mitochondrial RNA (mtRNA). These molecules activated the cGAS-STING and RIG-I-MAVS signaling pathways, respectively, thereby synergistically promoting the production of IFN-β and secretion into the extracellular matrix. Subsequently, IFN-β facilitated the polarization of macrophages in distant non-irradiated tumor microenvironment towards the M1 phenotype through activating STAT1. Furthermore, our findings indicate that high linear energy transfer (LET) carbon ions are significantly more effective in inducing the production of IFN-β and promoting macrophage polarization compared to low-LET X-rays. Thus, our findings provide insights into the intricate mechanisms by which mtDNA/RNA and IFN-β mediate RIAE, suggesting that IFN-β could be a promising target for provoking RT immunogenicity in patients with breast cancer and high-LET radiation might effectively elicit RIAE.