The collaborative transnational project focuses on establishing a multimodal comprehensive non-invasive biomarker for identifying hypoxia (a character of malignant growing solid tumours) to personalize radiation treatment. Hypoxia in many solid tumors and their microenvironments significantly contributes to resistance against the effects of radiotherapy (RT). Carbon ion RT (CIRT) and in general heavy ion RT are becoming a pivotal approach due to the superior efficacy in targeting hypoxia tumors compared to conventional photon RT. However, during the selection of radiotherapy treatment, specific traits such as hypoxia are not usually considered. The lack of comprehensive non invasive predictive biomarker hinders personalized approaches in RT. Hi-ROC compares genetic, transcriptomic, microbiota, cellular, microcirculation data and imaging features of patients with unresectable locally advanced lung cancer, high-risk head and neck cancer, are compared with data obtained from patients with operable retroperitoneal soft tissue sarcoma who were either cured or not cured by definitive or postoperative photon RT. The most useful biomarker will be chosen and used in a pilot study to address patients to either CIRT or photon RT, assessing the viability of the potential for future trials. A beta prototype for an in vitro medical device will be developed to determine clinically hypoxia non-invasively. Moreover, in vitro experiments and the optimization of an in-silico platform will be used to analyse hypoxia mechanisms and assess the potential of advanced RT techniques in overcoming it. Finally, Hi-ROC explores feasibility and digital twins potential (representation of real patient disease) in personalized RT providing a new biomarkers’ generation.