Unveiling Novel Targets in Lung Tumors for Enhanced Radiotherapy Efficacy: A Comprehensive Review

Radiotherapy is a cornerstone of lung cancer management, though its efficacy is frequently undermined by intrinsic and acquired radioresistance. This review examines the complexity of lung tumors, highlighting their potential as a reservoir of novel targets for radiosensitization. Ionizing radiation (IR) primarily exerts its effects through oxidative damage and DNA double-strand breaks (DSBs). Lung cancer cells, however, develop mutations that enhance DNA damage response (DDR) and suppress cell death pathways. Additionally, interactions between tumor cells and tumor microenvironment (TME) components-including immune cells, stromal cells, and molecular mediators such as cytokines, chemokines, and growth factors-contribute to resistance against IR. Understanding these intricate relationships reveals potential targets to improve radiotherapy outcomes. Promising targets include DDR pathways, immunosuppressive cells and molecules, hypoxia, proangiogenic mediators, and other key signaling pathways. This review discusses emerging strategies, such as combining radiotherapy with immunomodulators, hypoxia and proangiogenic inhibitors, DDR-targeting agents, and other innovative approaches. By offering a comprehensive analysis of the lung TME, this review underscores opportunities to enhance radiotherapy effectiveness through targeted radiosensitization strategies.