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Synergizing Radiotherapy and Immune Checkpoint Inhibitors in Malignant Solid Tumours: Mechanistic Insights and Translational Frontiers
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DOI：10.1017/erm.2026.10041.png)
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Abstract
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BackgroundRadiotherapy (RT) and immune checkpoint inhibitors (ICIs) have each transformed the treatment of malignant solid tumors (STs). Beyond direct tumor killing; RT remodels the tumor microenvironment (TME); promotes antigen release; and enhances immune activation. ICIs targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4); programmed cell death protein 1 (PD-1); and programmed cell death ligand 1 (PD-L1) restore antitumor immunity by reversing T cell exhaustion. Increasing evidence indicates that RT can synergize with ICIs through mechanisms such as the abscopal effect; immunogenic cell death (ICD); and activation of the cyclic guanosine monophosphate–adenosine monophosphate (cGMP–AMP) synthase–stimulator of interferon genes (cGAS–STING) pathway.MethodsThis review summarizes current radiobiological; immunological; and clinical evidence regarding the synergistic effects of RT and ICIs in malignant STs; with a focus on underlying mechanisms; recent clinical advances; and translational challenges.ResultsRT can enhance tumor immunogenicity; promote immune priming; and reshape the TME to improve the efficacy of ICIs. Synergy between RT and ICIs is associated with ICD induction; cGAS‒STING activation; enhanced systemic antitumor immunity; and modulation of immune cell infiltration and checkpoint signaling. Clinical studies across multiple STs have shown encouraging efficacy and manageable safety; although outcomes vary according to tumor type; disease stage; radiation schedule; and patient selection.ConclusionsRT combined with ICIs is a promising therapeutic strategy for malignant STs. Further optimization of treatment regimens and biomarker-guided patient selection will be essential to maximize clinical benefit and enable more precise combination therapies.
Keywords:
abscopal effect
combination therapy
cGAS-STING pathway
immune checkpoint inhibitors
immunogenic cell death
radiotherapy
translational oncology
tumour immune microenvironment
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