Radiotherapy is a common treatment for cancer, with its effectiveness largely dependent on the activation of anti-tumor immunity. This immune activation allows radiation to be combined with immune checkpoint blockade (ICB) therapies for improved responses in both irradiated and non-irradiated tumors. However, the synergy between radiotherapy and ICB remains limited, emphasizing the need for a deeper understanding of how the intrinsic responses of irradiated cancer cells lead to systemic immune activation. In this study, we show that cancer cells employ RNASEL, an endoribonuclease, to propagate radiation-induced RNA danger signals for systemic immune responses. Following radiation, an accumulation of endogenous double-stranded RNAs in cancer cells is coupled to the activation of RNASEL and an altered RNA composition within tumor-released small extracellular vesicles (sEVs). This RNA alteration includes an RNASEL-mediated reduction of immune inhibitory circular RNAs (circRNAs), leading to a net increase in immunostimulatory activity of sEV RNAs when taken up by dendritic cells (DCs). The RNA sensor MDA5 recognizes these sEV RNAs in DCs, enhancing DC activation and improving CD8+ T cell infiltration into tumors, which contributes to radiation’s ability to boost ICB efficacy on non-irradiated tumors. Thus, by diminishing circRNAs, RNASEL activation after radiation augments immunogenicity of sEV RNAs to enhance the ICB response. In patients receiving radiotherapy, both increased levels of RNASEL-cleaved RNA fragments and decreased levels of circRNA are observed in sEVs collected from serum, further supporting the role of RNASEL in promoting the immunostimulatory capability of sEV RNAs after radiation. This work highlights the significance of specific RNA species as immunomodulatory signals in radiation-induced anti-tumor immunity.