Radiogenomics of Stereotactic Radiotherapy: Genetic Mechanisms Underlying Radiosensitivity, Resistance, and Immune Response

Stereotactic body radiotherapy (SBRT) delivers ablative radiation doses with sub-millimeter precision. Radiogenomic studies, meanwhile, provide insights into how tumor-intrinsic genetic factors influence responses to such high-dose treatments. This review explores the radiobiological mechanisms underpinning SBRT efficacy, emphasizing the roles of DNA damage response (DDR) pathways, tumor suppressor gene alterations, and inflammatory signaling in shaping tumor radiosensitivity or resistance. SBRT induces complex DNA double-strand breaks (DSBs) that robustly activate DDR signaling cascades, particularly via the ATM and ATR kinases. Tumors with proficient DNA repair capabilities often resist SBRT, whereas deficiencies in key repair genes can render them more susceptible to radiation-induced cytotoxicity. Mutations in tumor suppressor genes may impair p53-dependent apoptosis and disrupt cell cycle checkpoints, allowing malignant cells to evade radiation-induced cell death. Furthermore, SBRT provokes the release of pro-inflammatory cytokines and activates innate immune pathways, potentially leading to immunogenic cell death and reshaping the tumor microenvironment. Radiogenomic profiling has identified genomic alterations and molecular signatures associated with differential responses to SBRT and immune activation. These insights open avenues for precision radiotherapy approaches, including the use of genomic biomarkers for patient selection, the integration of SBRT with DDR inhibitors or immunotherapies, and the customization of treatment plans based on individual tumor genotypes and immune landscapes. Ultimately, these strategies aim to enhance SBRT efficacy and improve clinical outcomes through biologically tailored treatment. This review provides a comprehensive summary of current knowledge on the genetic determinants of response to stereotactic radiotherapy and discusses their implications for personalized cancer treatment.