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.