Mitochondria and Radioresistance Publisher



Fadavi P ; Taghizadehhesary F
Source: Mitochondria and Cancer: From Basic Science to Clinical Applications - Understanding Pathogenesis, Therapy Resistance, and Disease Relapse Published:2026

Abstract

Radioresistance remains a major obstacle in the effective treatment of cancer with radiotherapy. This chapter delves into the multifaceted strategies employed by cancer cells to evade radiation-induced cell death, with a specific emphasis on the central role of mitochondria. Cancer cells exploit several adaptive mechanisms—including enhanced DNA repair, cell cycle arrest, reactive oxygen species (ROS) scavenging, autophagy, epithelial-mesenchymal transition (EMT), angiogenesis, and immune suppression—to increase their survival following radiation exposure. These processes are tightly regulated by the tumor microenvironment (TME), which provides metabolic support, promotes hypoxia, modulates immune responses, and triggers cellular signaling pathways that foster resistance. Recent research has identified mitochondria as pivotal regulators of radioresistance, not only by supplying ATP for DNA repair and antioxidant defenses but also by modulating redox balance, cell death pathways, and immune evasion. Mitochondrial adaptations include increased biogenesis, altered dynamics (fusion/fission), and interactions with both host immune cells and the microbiome. Tumor-infiltrating microbes can further enhance radioresistance by promoting mitochondrial function and metabolic reprogramming. Additionally, tumor-infiltrating nerves and adrenergic signaling have been implicated in enhancing mitochondrial activity and cellular stemness, further contributing to resistance. Taken together, this chapter presents an integrated framework connecting mitochondrial metabolism to the diverse hallmarks of radioresistance. Understanding the centrality of mitochondria in these processes not only enhances our comprehension of therapy resistance but also reveals new therapeutic opportunities. Targeting mitochondrial pathways and their interactions with the TME may offer promising strategies to overcome radioresistance and improve radiotherapy outcomes across a range of malignancies. © 2026 Elsevier Inc. All rights reserved.