Superior tumor cell killing by oxygen ion beam irradiation compared to carbon ions and photons in pancreatic Cancer cells - An in vitro investigation.

Pancreatic cancer remains one of the most treatment-refractory malignancies, displaying profound resistance to chemotherapy and radiotherapy. While the benefit of photon radiotherapy remains debated, heavy-ion modalities such as carbon ions show promise in overcoming radioresistance. Here, we extend this paradigm by evaluating oxygen-ion beam irradiation in pancreatic cancer cells and directly comparing its efficacy with carbon ions and photons. Oxygen ions induce higher clonogenic cell killing in human pancreatic cancer cells, with a relative biological effectiveness (RBE) around two times higher for oxygen ions than for carbon ions. Moreover, their growth-inhibitory effects are substantially less dependent on gemcitabine-mediated radiosensitization than those of carbon ions or photons. Mechanistically, oxygen-ion irradiation induces greater direct and complex DNA damage, slows down DNA repair kinetics, and augments apoptosis following combined gemcitabine treatment, accompanied by sustained activation of DNA damage response pathways. These findings delineate the distinct radiobiological advantages of oxygen ion beam irradiation in pancreatic cancer and highlight their potential as a powerful modality to overcome radioresistance, providing a compelling rationale for further translational and clinical exploration.