Modern oncology increasingly relies on personalized strategies that aim to customize medical interventions, using both tumor biology and clinical features to enhance efficacy and minimize adverse effects. In recent years, precision medicine has been implemented as part of systemic therapies; however, its integration into radiation therapy (RT) is still a work in progress. Conventional RT treatment plans are based on the Linear Quadratic (LQ) model and utilize standardized alpha and beta ratios (α/β), which ignore the high variability in terms of treatment response between and within patients. Recent advances in radiobiology, as well as general medical technologies, have also driven a shift toward more tailored approaches, including in RT. This review provides an overview of current knowledge and future perspectives for the personalization of RT, highlighting the role of tumor and patient-specific biomarkers, advanced imaging techniques, and novel therapeutic approaches. As an alternative to conventional RT modalities, hadron therapy and Flash RT are discussed as innovative approaches with the potential to improve tumor targeting while sparing normal tissues. Furthermore, the synergistic combination of RT with immunotherapy is discussed as a potential strategy to support antitumor immune responses and overcome resistance. By integrating biological insights, technological innovation, and clinical expertise, personalized radiation therapy may significantly advance the precision oncology paradigm.

Tumour hypoxia is a major cause of radiotherapy (RT) failure and is associated with increased tumour biological aggressiveness, an increased risk of recurrence, and reduced patient survival. Oxygen plays a fundamental role in the effectiveness of RT. Ionising radiation exerts its cytotoxic effect both directly, by inducing DNA damage, and indirectly, through the production of reactive oxygen species (ROS). Under normoxic conditions, oxygen reacts with radiation-generated free radicals, stabilising the DNA damage and making it irreversible. Conversely, in hypoxic cells, some of the radiation-induced damage can be repaired, resulting in a significant reduction in therapeutic efficacy (Oxygen Enhancement Ratio - OER). In addition to its direct effect on radiation sensitivity, hypoxia induces profound molecular changes driven by the hypoxia-inducible factor 1α (HIF-1α), thus promoting glycolytic metabolism and contributing to the acquisition of more invasive and metastatic characteristics. Moreover, hypoxia increases DNA repair capacity, cell cycle disruption, the selection of more aggressive cell clones and the induction of an immunosuppressive microenvironment, causing radioresistance phenotype. In recent years, several strategies, such as the use of high linear energy transfer (LET) radiation, radiosensitizers, as well as drugs directed against hypoxia-associated molecular target have been developed to counteract tumour hypoxia and improve its radiosensitivity. At the same time, advanced molecular imaging techniques now allow us to identify and quantify hypoxic regions within the tumour, promoting personalized therapeutic approaches. Hypoxia represents a crucial determinant of tumour radioresistance. Understanding the biological mechanisms that regulate it not only explains the reduced efficacy of RT in many solid tumours but also offers new opportunities to develop targeted therapeutic strategies capable of improving local disease control and patient clinical outcomes.

Background: Adult diffuse gliomas represent one of the most aggressive types of brain tumors. Proton therapy offers a minimally invasive treatment option whose biological effectiveness may be enhanced through nuclear reactions involving boron atoms, leading to the emission of high-LET α-particles. In this study, we investigated the potential enhancement of radiation-induced damage of a novel boron-conjugated, ATP-competitive SRC kinase inhibitor, in the U-87 MG glioma cell line and its isogenic cell line stably expressing the IDH1 R132H mutation. Methods: Glioma cells were exposed to either proton or X-ray irradiation to assess whether any enhancement associated with this boron-delivery strategy was specific to proton interactions. Cell survival assays and analyses of DNA damage responses were conducted in both cell lines. Results: While no significant synergistic effects were observed in survival endpoints, differences emerged at the level of early DNA damage effects, with IDH1-mutant glioma cells displaying an enhanced acute response following combined treatment with proton irradiation. Conclusions: These findings support further pharmacological development of boron-based SRC-targeted strategies and underscore the importance of tailoring therapeutic approaches to specific glioma molecular subtypes.

Tumour hypoxia is a major cause of radiotherapy (RT) failure and is associated with increased tumour biological aggressiveness, an increased risk of recurrence, and reduced patient survival. Oxygen plays a fundamental role in RT effectiveness. Ionizing radiation exerts its cytotoxic effect both directly, by inducing DNA damage, and indirectly, through the production of reactive oxygen species (ROS). Under normoxic conditions, oxygen reacts with radiation-generated free radicals, stabilizing the DNA damage and making it irreversible. Conversely, in hypoxic cells, some of the radiation-induced damage can be repaired, resulting in a significant reduction in therapeutic efficacy (Oxygen Enhancement Ratio—OER). In addition to its direct effect on radiation sensitivity, hypoxia induces profound molecular changes driven by the hypoxia-inducible factor 1α (HIF-1α), thus promoting glycolytic metabolism and contributing to the acquisition of more invasive and metastatic characteristics. Moreover, hypoxia increases DNA repair capacity, cell cycle disruption, the selection of more aggressive cell clones and the induction of an immunosuppressive microenvironment, causing radioresistance phenotype. In recent years, several strategies, such as the use of high linear energy transfer (LET) radiation, radiosensitizers, as well as drugs directed against hypoxia-associated molecular target have been developed to counteract tumour hypoxia and improve its radiosensitivity. At the same time, advanced molecular imaging techniques now allow us to identify and quantify hypoxic regions within the tumour, promoting personalized therapeutic approaches. Hypoxia represents a crucial determinant of tumour radioresistance. Understanding the biological mechanisms that regulate it not only explains the reduced efficacy of RT in many solid tumours but also offers new opportunities to develop targeted therapeutic strategies capable of improving local disease control and patient clinical outcomes.