Overcoming Radiation Resistance: Ferroptosis Induction to Sensitize Solid Tumors to Radiation Therapy

Radiation therapy (RT) is a mainstay of treatment for a myriad of cancers, often utilized for tumors that are unable to be resected, as well as an adjunct to surgery and chemotherapy. Unfortunately, many cancers are resistant to RT-induced damage and subsequent cell death. This has spurred the pursuit of novel radiation sensitizers that could potentiate the effects of this widely used and important treatment modality. Since its discovery as a regulated cell death mechanism in 2012, ferroptosis has been studied for its connection to cancer and other known oxidative pathways. With this, the interplay between RT and ferroptosis in cancer has recently begun to be explored. Radiation increases reactive oxygen species (ROS), facilitates lipid peroxidation, and releases free ferrous iron, all of which directly impact the ferroptotic pathway. In conjunction, RT has been shown to induce the expression of ferroptosis-related molecules (e.g., SLC7A11, GPX4) through the P62-KEAP1-NRF2 pathway, thereby preventing cell death via ferroptosis. The use of ferroptosis inducers (FINs) to block these antioxidant mechanisms is a promising area of study as pharmacological radiosensitizers to improve the efficacy of RT and patient outcomes. In this comprehensive narrative review, the molecular connections between ferroptosis, cancer, and radiation will be discussed, the preponderance of existing literature investigating the potential of FINs as radiosensitizers will be presented, and possible areas of future study will be offered.