Radiotherapy as an immunomodulator in cancer: Synergy with immunotherapy and roadmap for optimization

Cancer remains a major global health challenge, with an estimated 19.3 million new cases and ∼10 million deaths annually, and incidence projected to reach 28.4 million by 2040. Used in over half of patients, radiotherapy has progressed from a purely cytotoxic treatment to an immunomodulatory modality that can function as an “in situ vaccine” and synergize with immunotherapy. This review summarizes the bidirectional immune effects of radiotherapy, highlighting pro-immunogenic mechanisms such as immunogenic cell death with DAMP (damage-associated molecular pattern) release, cGAS–STING–type I interferon activation, enhanced antigen processing/presentation, chemokine-driven T-cell recruitment, and treatment-induced PD-L1 upregulation that may be leveraged by immune checkpoint blockade, as well as counteracting immunosuppressive processes including Treg (regulatory T cell)/MDSC (myeloid-derived suppressor cell) enrichment, suppressive cytokines, radiation-induced lymphopenia, and metabolic constraints. We also synthesize clinical evidence supporting RT–immune checkpoint inhibitor combinations (exemplified by PACIFIC establishing durvalumab after chemoradiotherapy for stage III NSCLC with 5-year OS of 42.9% versus 33.4% in the placebo arm), and discuss key optimization strategies involving dose-fractionation, field design with lymphocyte sparing, sequencing/timing, multimodal regimens, biomarker-guided patient selection, and toxicity/QoL management. Finally, we outline future directions toward precision radiotherapy through multi-omics integration, AI-assisted prediction, real-time immune monitoring, and novel immunotherapies and trial designs to enable individualized, biomarker-informed regimens with improved efficacy and reduced toxicity.