From DNA damage to systemic immunity: Interaction networks in radio-immunotherapy

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, yet primary and acquired resistance continues to limit durable benefit. Radiotherapy, long valued for its direct cytotoxicity, is now recognized as a powerful immunomodulator that remodels the tumor microenvironment (TME) and can convert immunologically "cold" tumors into "hot" ones. However, ionizing radiation exerts both immune-activating and immunosuppressive effects that vary with dose, fractionation, and biological context, and the therapeutic synergy of radiotherapy and immunotherapy ultimately depends on the molecular interactions that govern these responses. In this review, we first examine how radiation shapes the inflammatory response and both innate and adaptive immunity, including the immunostimulatory potential of low-dose radiation on cellular and humoral immunity, the abscopal and RadScopal effects, cGAS-STING-mediated nucleic-acid sensing, and immunogenic cell death. We then propose molecular interactions as a unifying framework for dissecting therapeutic response and resistance, systematically analyzing protein-protein, protein-DNA, gene-drug, and protein-drug interactions that regulate key signaling pathways and define actionable therapeutic targets. Building on this framework, we summarize current targeting strategies including cytokine therapy, antibody-based immunotherapy and immune checkpoint blockade, and tumor vaccines and review clinical evidence on combined radio-immunotherapy across tumor types. Finally, we discuss critical challenges and future directions, including the optimal sequencing and scheduling of the two modalities, the choice of radiation dose and particle type, the "badscopal" effect, biomarker-guided patient selection, and nanotechnology-enabled delivery. We argue that a systems-level shift from a "local" to a "systemic" view of radiotherapy, grounded in a deeper mastery of these molecular interaction networks, is essential for designing the next generation of precision radio-immunotherapy.