Exploiting DNA Repair Vulnerabilities in Particle Therapy

Particle therapy, including proton and carbon ion radiotherapy, represents a major advancement in cancer treatment due to its unique physical properties. By exploiting high linear energy transfer (LET), particle beams induce complex, clustered DNA damage that challenges canonical repair mechanisms. Growing evidence now highlights a central role of DNA damage response (DDR) pathways in determining treatment efficacy, radiosensitivity, and normal tissue toxicity. Understanding and exploiting these interactions is essential to unlock the full therapeutic potential of
particle therapy.

This Research Topic aims to bridge the gap between mechanistic radiobiology and clinical application by bringing together cutting-edge research on how proton and heavy ion radiation interact with DNA repair pathways and how these interactions can be leveraged for therapeutic benefit. We seek contributions that advance our understanding of DDR mechanisms in particle therapy, identify predictive biomarkers for patient stratification, and explore novel combination strategies to overcome radioresistance. A key goal is to translate molecular insights into clinically actionable approaches that improve tumor control while minimizing adverse effects.

We welcome original research, reviews, perspectives, and brief reports addressing, but not limited to, the following themes:
• Molecular mechanisms of DNA repair (NHEJ, HR, alt-EJ, Fanconi anemia pathway) in response to proton and carbon ion irradiation.
• Combination strategies using DNA repair inhibitors (PARP, ATR, ATM, DNA-PK inhibitors) with particle therapy.
• Predictive biomarkers of radiosensitivity, resistance, and normal tissue toxicity.
• Integration of multi-omics approaches (genomics, transcriptomics, proteomics) for patient stratification.
• Role of tumor hypoxia and oxygen enhancement ratio in DDR and particle therapy response.
• DNA repair–immune signaling crosstalk (cGAS-STING, interferon pathways) following particle irradiation.
• Targeting cancer stem cells through DNA repair vulnerabilities.
• Relative biological effectiveness (RBE) optimization and LET-guided treatment planning.
• Clinical outcomes linked to DNA repair proficiency across tumor types, including radioresistant malignancies (sarcoma, glioblastoma, head and neck, pediatric tumors).
• Radiogenomic modeling and biological optimization of particle therapy.
• Bystander and abscopal effects related to DNA damage signaling.

Submissions should provide mechanistic insights, translational findings, or clinical correlations and may involve in vitro, in vivo, or patient-derived data. Multidisciplinary studies incorporating computational modeling, systems biology, or combined-modality approaches are strongly encouraged. We particularly welcome contributions that connect laboratory findings to clinical endpoints such as tumor control, treatment toxicity, and long-term survivorship.

Please note: manuscripts consisting solely of bioinformatics, computational analysis, or predictions from public databases without independent validation (clinical cohort, or biological validation in vitro/in vivo) are not suitable for this collection.

Keywords: Particle Therapy, Proton Therapy, Carbon Ion Radiotherapy, DNA Repair, Radiosensitivity, Biomarkers, Radiobiology, Radiogenomics, Relative Biological Effectiveness (RBE), Personalized Radiotherapy

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.