“Hypoxia in tumors and their microenvironments significantly contributes to resistance gainst photon-based radiotherapy in many solid cancers. In this context, heavy ion RT, specially carbon ion RT (CIRT), is becoming increasingly a pivotal approach due to its superior efficacy in targeting hypoxia tumors compared to photon RT. However, RT protocols typically prioritize factors like tumor stage and histotype over specific traits such as hypoxia when selecting treatments. While this approach streamlines therapeutic decisions, it falls short of achieving the best therapeutic results for patients. A significant challenge hindering personalized approaches in selecting patients for CIRT is the lack of a comprehensive non-invasive diagnostic/predictive biomarker. Our collaborative translational project (Hi-ROC) focuses on establishing a multimodal and comprehensive non-invasive biomarker/signature for identifying hypoxia at the individual level. This will involve comparing genetic, transcriptomic, microbiota, cellular, microcirculation, and imaging features of patients with unresectable locally advanced lung cancer, high-risk head and neck cancer, and large operable retroperitoneal soft tissue sarcoma who were either cured or not cured by photon RT. The biomarker will be used in a pilot study to select patients for either CIRT or photon RT, assessing the viability of the potential for future clinical trials. Additionally, we will develop a Beta-Prototype for an in vitro medical device for non-invasive determination of clinically relevant hypoxia. Our project also entails deepening our understanding of hypoxia mechanisms through in vitro experiments and optimizing an in-silico platform to assess the potential of advanced RT techniques and technologies (beyond C-ions) in overcoming hypoxia. Finally, we will explore the use of feasibility and potential of digital twins in personalized radiation oncology, representing a new generation of biomarkers.”