Dose Heterogeneity Reduces Radiation Oxygen Dependence in Both Tumor and Healthy Tissues: The Case of Proton Minibeam Radiation Therapy.

The study investigates whether proton minibeam radiation therapy (pMBRT), characterized by spatially modulated high-dose and low-dose regions, can reduce the oxygen dependence of radiation response in tumors and normal tissues compared with conventional proton therapy (CPT). Using glioblastoma-bearing and healthy rats exposed to different oxygen levels during irradiation, researchers analyzed survival, immune response, and tissue effects. While CPT outcomes varied with oxygen supplementation—improving survival but impairing immune infiltration—pMBRT results remained stable regardless of oxygen concentration. Tumor-bearing animals treated with pMBRT showed strong T-cell infiltration and consistent survival independent of oxygenation, whereas CPT displayed clear oxygen sensitivity. Likewise, pMBRT produced minimal damage to brain and bone tissues and did not alter cognitive or motor functions in healthy animals.
The findings indicate that the extreme peak doses in pMBRT may overcome the classical oxygen enhancement effect by effectively eradicating hypoxic, radioresistant tumor cells while sparing normal tissue. This suggests distinct radiobiological mechanisms from conventional radiation therapy, potentially due to high ionization density within minibeam peaks. Importantly, oxygen supplementation during pMBRT did not increase toxicity, supporting its safety for clinical use—especially in pediatric or hypoxic tumor cases.
In conclusion, pMBRT demonstrates reduced dependence on tissue oxygenation and maintains therapeutic efficacy with minimal side effects. The results highlight pMBRT as a promising approach for treating hypoxic, resistant tumors, meriting further exploration of its combination with immunotherapies to enhance tumor control and long-term outcomes.

International Journal of Radiation Oncology, Biology, Physics – Accepted June 15, 2025; Published online June 27, 2025 – DOI: 10.1016/j.ijrobp.2025.06.3859