Immune and inflammatory radiogenomics of radiotherapy-induced normal-tissue toxicity: genetic susceptibility, mechanisms, risk prediction, and clinical translation.

Radiotherapy is indispensable for cancer control, yet acute and late normal-tissue toxicities remain major limits to treatment intensity and survivorship. Considerable interindividual variation persists after clinical and dosimetric factors are considered, motivating radiogenomic studies of inherited susceptibility. This review compares common and rare germline variation, association and sequencing designs, polygenic risk scores, and functional evidence through an immunological framework. Radiation-induced DNA damage and organelle stress release danger-associated signals and cytosolic DNA that engage pattern-recognition pathways, including cGAS-STING, and initiate endothelial and epithelial inflammatory programs. Cytokines, chemokines, inflammasomes, recruited myeloid cells, lymphocytes, senescent cells, and fibroblasts then determine whether injury resolves or progresses to chronic immune dysregulation and fibrosis. Germline variants may modify these responses, but pathway plausibility is not equivalent to variant-specific causality. The strongest evidence combines a replicated clinical association with dose adjustment, regulatory annotation, allele-specific perturbation, and validation in organ-relevant immune-stromal models. Integrated prediction should combine genomic susceptibility with normal-tissue imaging, dose-volume exposure, baseline inflammatory state, comorbidity, and systemic therapy. Germline associations with checkpoint-inhibitor toxicity provide a rationale for studying radio-immunotherapy, although radiation-specific genetic interactions remain unvalidated. No current common variant or polygenic score justifies reducing curative dose or target coverage. Near-term translation is more appropriately directed toward risk-adapted surveillance, supportive care, and genotype-enriched prevention trials. An immune-centered radiogenomic framework can connect inherited susceptibility to damage sensing, inflammatory amplification, resolution failure, and tissue remodeling while preserving the distinction between mechanistic evidence and clinical utility. Graphical summary: inherited susceptibility modifies the sequence from radiation-induced damage sensing and immune activation to resolution, repair, or chronic inflammation and fibrosis.