Harnessing ferroptosis as a potential strategy for radiosensitization and cancer control

Cancer continues to be one of the primary causes of deaths across the world. One of the key factors that make it difficult to manage the disease is therapy resistance which is commonly attributed to anti-apoptosis signaling. Ferroptosis, an iron-dependent form of regulated cell death (RCD) characterized by lipid peroxidation, reactive oxygen species (ROS) accumulation, glutathione (GSH) depletion, and glutathione peroxidase 4 (GPX4) inactivation, has gained traction as a potential approach to circumvent this resistance. It has been stated that Ionizing radiation (IR) leads to the occurrence of ferroptosis through generation of redox disequilibrium, suppression of Xc− system, decrease in the level of GSH, downregulation of GPX4 and lipids peroxidation by means of acyl-CoA synthetase long-chain family member 4 (ACSL4). Furthermore, p53, ATM and cGAS-STING signaling pathway play a role in radiation-mediated ferroptosis and anti-tumor immunity Moreover, p53, ATM, and cGAS-STING pathway may act to facilitate radiation-induced ferroptosis and antitumor immunity. In this article, we first provide a general overview of the concept of ferroptosis and its molecular features. Then, the role of radiation in the induction of ferroptosis and the pathways involved in this process, including changes in redox balance and lipid peroxidation, were examined. Also, the effect of the physical characteristics of radiation, especially LET, on the induction of ferroptosis was analyzed. Moreover, the combination of radiotherapy (RT) with other cancer treatments like photodynamic therapy (PDT) has been studied. Finally, the role played by RT in collaboration with various types of cell death, particularly immunogenic cell death (ICD), has been studied in order to understand the synergy of both therapies in improving antitumor therapy. Finally, the role of nanomaterials in combination with radiation to enhance the induction of ferroptosis and improve the therapeutic response was also investigated. Overall, this review suggests that combining RT with ferroptosis-based strategies, could provide new horizons for overcoming therapeutic resistance and increasing the effectiveness of cancer treatment.