Synergizing Radiotherapy and Immune Checkpoint Inhibitors in Malignant Solid Tumours: Mechanistic Insights and Translational Frontiers.

[BACKGROUND] Radiotherapy (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.

[METHODS] This 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.

[RESULTS] RT 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.

[CONCLUSIONS] RT 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.