Hypoxia and intrinsic radiosensitivity: Exploring mechanisms in radiation resistance of cancers and biomarkers for enhanced treatment strategies

Among all the treatment modalities, despite the development of targeted treatments, radiotherapy is still considered one of the most effective treatment approaches. While this modality is highly effective in tumor control, it still faces resistance in cancer cells through complex mechanisms. Hypoxia has been considered one of the important characteristics of solid tumors, effectively impacting therapeutic response and a challenge for treatment because of radiation resistance, poor prognosis, and reduced effectiveness of radiation therapy. Hypoxia may facilitate a series of adaptive responses by which tumors survive and progress despite radiation therapy, acting through several pathways: stabilizing hypoxia-inducible factors, metabolic reprogramming, disruption of DNA damage signaling, genomic instability, and cell cycle arrest. More specifically, hypoxia PET, MRI-based oxygenation measurements, and the integration of artificial intelligence with imaging approaches have considerably given valuable information on tumor oxygenation and related mechanisms of radiation resistance, supplemented by HIF-1α, CAIX, VEGF, GLUT1, and some hypoxia-associated microRNAs. This review discusses the key molecular and cellular pathways taking part in the processes leading to radioresistance brought about by hypoxia and highlights biomarkers able to predict radiation response. A deep understanding of these mechanisms may enable the development of novel therapeutic approaches to overcome hypoxia-induced radioresistance, thereby improving personalized cancer therapy.