Overcoming Radioresistance by Targeting Hypoxia
Year: 2026
Type: article
Abstract: 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.
Source: Molecules
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,258
OpenAlex ID: W7214728730