Intratumoral co-activation of ERV transcription and RNA virus-sensing is associated with radiotherapy-induced immune response and abscopal effect

Abstract Radiotherapy (RT) transforms tumors into in situ vaccines that trigger antitumor immunity. However, the relevant pathways remain largely unelucidated, limiting clinical translation. Herein, we developed a hybrid dry-lab/wet-lab approach integrating systems-level immune phenotypes following homogenous or spatially fractionated RT (SFRT) with transcriptomic profiling of irradiated tumors. By combining feature extraction with machine-learning, including multilayer perceptron modeling, we ranked predictors of immune infiltration and patient survivability for each RT type. RT induced coordinated upregulation of viral RNA-binding proteins (OASes and RIG I-like receptors) along with endogenous retrovirus (ERV) RNAs predominately 400–800 bp long, which may serve as their ligands. During abscopal responses, OASes and ERV transcripts were co-induced and shared between irradiated and distant tumors. SFRT triggered earlier activation of OAS signaling versus homogenous RT. Our findings highlight ERVs as underappreciated contributors to RT-induced antitumor immunity and their interactions with intratumoral cytosolic sensors as potential novel biomarkers in precision radio-oncology.