<p>Radiotherapy (RT) is a cornerstone of cancer therapy that exerts cytotoxic effects while also modulating anti-tumor immunity. RT-induced DNA damage can, under specific biological conditions, activate the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) and its downstream stimulator of interferon genes (STING) pathway, eliciting type I interferon (IFN-I) responses and dendritic cell-mediated T-cell priming. This signaling is tightly regulated by TREX1-mediated DNA degradation, apoptotic caspases, and chromatin-bound nuclear DNA, resulting in heterogeneous immune outcomes. Notably, tumors with mismatch repair deficiency, such as MLH1 loss, exhibit pre-existing cGAS-STING activity, in which RT primarily amplifies innate sensing. However, even in this context, excessive or sustained STING activation may paradoxically induce immune tolerance, and the clinical application of STING agonists remains constrained by dose-limiting toxicities and delivery challenges. Here, we review the context-dependent interplay between RT and the cGAS-STING axis, highlighting mechanistic regulation, tumor genetics, and the tumor microenvironment. We propose strategies for precision calibration of RT and STING agonist delivery to enhance anti-tumor immunity, enable cold-to-hot tumor transformation, and guide rational combination with immunotherapy.</p>