Low-dose radiotherapy remodels the tumor immune microenvironment via the cGAS–STING pathway: mechanisms, challenges, and combination therapy strategies

Low-dose radiotherapy (LDRT) has emerged as a promising immunomodulatory strategy by activating the cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS-STING) pathway, thereby reprogramming the tumor immune microenvironment (TIME). LDRT induces DNA damage and cytosolic dsDNA accumulation, leading to cGAS-STING activation and subsequent production of type I interferon and proinflammatory cytokines. Consequently, LDRT promotes dendritic cell maturation, enhances CD8⁺ T cell infiltration and cytotoxicity, repolarizes macrophages toward an anti-tumor, immunostimulatory phenotype, and suppresses myeloid-derived suppressor cells and regulatory T cells (Tregs). However, sustained cGAS–STING activation may paradoxically induce immunosuppression through PD-L1 upregulation, T cell exhaustion, and enrichment of inhibitory cells. Combining LDRT with immune checkpoint inhibitors, STING agonists, chemotherapy, or CAR-T cell therapy synergistically amplifies antitumor immunity by overcoming TIME suppression and fostering long-term immune memory. Challenges such as radiotherapy heterogeneity, dose optimization, and STING pathway mutations require precise strategies including image-guided radiotherapy, nanocarrier-based delivery, and biomarker-driven patient stratification. This review highlights the dual role of LDRT-mediated cGAS–STING signaling in TIME remodeling and provides a foundation for developing novel combinatorial immunotherapies. ① LDRT Activates cGAS–STING via DNA Damage. LDRT induces nuclear and mitochondrial DNA damage, releasing dsDNA into the cytosol. Cytosolic dsDNA is sensed by cGAS, triggering cGAMP synthesis and STING activation. ② Dual Signaling Axes Drive Immune Activation. STING activates IRF3 to promote IFN-I production, enhancing antigen presentation and T cell cytotoxicity. NF-κB activation induces proinflammatory cytokines and chemokines, recruiting immune cells. ③ TIME Remodeling from "Cold" to "Hot". Promotes dendritic cell maturation, CD8⁺ T cell infiltration, and macrophage M1 polarization. Suppresses immunosuppressive cells and cytokines. ④ Paradoxical Immunosuppressive Effects. Sustained cGAS–STING activation upregulates PD-L1, induces T cell exhaustion, and enriches inhibitory cells. Excessive IFN-I signaling may lead to immune tolerance and therapy resistance. ⑤ Synergistic Combinatorial Therapies. LDRT combined with immune checkpoint inhibitors enhances T cell activation and reverses immunosuppression. With STING agonists, it amplifies pathway activation and systemic antitumor immunity. And with chemotherapy/CAR-T therapy, it improves immune cell infiltration and target recognition. ⑥ Challenges and Optimization Strategies. Radiotherapy heterogeneity and hypoxic regions limit efficacy. Solutions: Image-guided radiotherapy, spatial fractionation, nanocarriers for agonist delivery. Personalized dosing and timing based on tumor type and STING pathway status. ⑦ Future Directions. Develop STING pathway biomarkers for patient stratification. Explore novel formulations and gene editing to restore STING function. Integrate multimodal imaging and single-cell technologies to optimize combination regimens.