Exploring Radioresistance Mechanisms and Radiosensitization in Human Cancers: Potential Biomarkers of Radiotherapy Response

Radiotherapy represents an effective treatment for different cancer types and is continuously evolving through the development of more accurate therapeutic approaches, although radioresistance and treatment failure still remain important challenges. Early indications regarding the individual response to radiotherapy are needed in order to estimate its possible clinical impact and to allow treatment adaptation when necessary. Current knowledge on the molecular and cellular mechanisms involved in radioresistance and radiosensitization is discussed together with recent preclinical and clinical evidence on potential biomarkers that may provide information on radiotherapy response and subsequent treatment outcome. The available evidence indicates that the response to irradiation is influenced by both tumor-intrinsic mechanisms and changes occurring in the tumor microenvironment, with their contributions varying according to cancer type and molecular background. Although several molecular and cellular biomarkers have been associated with radiosensitivity, radioresistance, recurrence, or treatment outcome, their predictive value appears to remain dependent on tumor type and biological context. Among them, secreted phosphoprotein 1 (SPP1) expression was recently found to be predictive for radiotherapy follow-up in both cervical cancer and hypopharyngeal squamous cell carcinoma. Additional clinical validation is required to establish which of these candidate biomarkers may provide reliable information before or during treatment and may allow earlier adaptation of radiotherapy towards improved clinical outcome and patients’ quality of life.