DAMP Signaling and Immunogenic Cell Death in Glioblastoma: Radiotherapy-Induced Immune Reprogramming and Opportunities for Personalized Treatment

Glioblastoma (GBM) remains among the most treatment-refractory human malignancies, shaped by profound molecular heterogeneity, extensive genomic instability and an immunosuppressive tumor microenvironment. Radiotherapy represents a cornerstone of current management; however, its therapeutic benefit is frequently limited by adaptive resistance and ineffective antitumor immunity. Emerging evidence indicates that ionizing radiation acts not only as a cytotoxic modality, but also as a potent immunological trigger through the release of damage-associated molecular patterns (DAMPs) and the induction of immunogenic cell death (ICD). In this review, we synthesize recent advances describing how canonical DAMPs—including HMGB1, ATP, calreticulin exposure, mitochondrial and nuclear DNA fragments—coordinate innate and adaptive immune activation via TLR-, RAGE- and cGAS–STING-dependent pathways. We further discuss the dual nature of DAMP signaling, which can either promote durable antitumor immunity or foster chronic inflammation, myeloid reprogramming and tumor tolerance, depending on radiation dose, fractionation, tumor context and concomitant therapies. Special emphasis is placed on how different radiation qualities, particularly proton versus photon irradiation, differentially modulate DAMP release, ICD dynamics and microenvironmental remodeling. Finally, we highlight translational opportunities to exploit DAMP-related signatures as liquid-biopsy biomarkers of response, as rational selectors for combination strategies (including immunotherapy and radiosensitizers), and as biological guides for personalized and adaptive radiotherapy in GBM. Collectively, DAMP-centered radiobiology provides a conceptual framework to integrate immunity into radiation planning and may enable a new generation of biologically informed treatment strategies for glioblastoma.