Systematic evidence review on radiosensitizers and the abscopal effects of radiotherapy

Abstract

BACKGROUND: The abscopal effect, defined as regression of non-irradiated tumors following localized radiotherapy (RT), is increasingly recognized as an immune-mediated phenomenon. Radiosensitizers may enhance this effect by amplifying radiation-induced immunogenicity and systemic anti-tumor immunity. METHODS: A systematic literature search for studies within PubMed/MEDLINE, Scopus, and Web of Science, covering a period from January 2015 to April 2026, was conducted. Studies eligible for inclusion were those that examined RT combined with radiosensitizing approaches and documented abscopal responses or outcomes relating to systemic anti-tumor immunity. RESULTS: Thirty-one preclinical studies met the inclusion criteria. Most radiosensitizers enhanced RT efficacy through increased DNA damage, reactive oxygen species (ROS) generation, hypoxia modulation, activation of the cGAS-STING pathway, and induction of immunogenic cell death (ICD). Enhanced dendritic cell maturation, increased CD8+ T-cell infiltration, elevated pro-inflammatory cytokine production, and reduction of immunosuppressive cell populations were frequently reported. Nanoparticle (NP)-based radiosensitizers and combinations with immune checkpoint inhibitors demonstrated the strongest and most consistent abscopal responses. However, several studies achieved local radiosensitization without meaningful systemic tumor regression. CONCLUSIONS: To successfully achieve radio-immune abscopal effects, tumoral radiosensitivity, immune system activation and alteration of tumor microenvironment need to occur together. More translational and clinically relevant research should generate systematic and robust evidence of treatment sequencing in different experimental frameworks and to determine durable predictive biomarkers for systemic response.