Mechanisms Underlying Radioresistance and Reversal Strategies in Non-Small Cell Lung Cancer

Radiotherapy (RT) continues to be a fundamental component in the management of non-small cell lung cancer (NSCLC). Nevertheless, some NSCLC patients do not attain optimal therapeutic outcomes due to the emergence of radioresistance. Improving the effectiveness of RT in NSCLC necessitates a thorough comprehension of the mechanisms that lead to radioresistance. This review delineates various potential mechanisms of radioresistance in NSCLC, encompassing augmented DNA damage repair, cell cycle dysregulation, cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT), tumor hypoxia, an immunosuppressive tumor microenvironment (TME), dysregulation of cell death pathways, metabolic reprogramming, exosome-mediated signaling, genetic mutations, aberrant activation of signaling pathways, and epigenetic modifications. In addition, this study explores various novel strategies aimed at enhancing the radiosensitivity of NSCLC and provides a concise overview of potential biomarkers predictive of RT response, which may contribute to the development of innovative combination therapies to address radioresistance and improve patient outcomes.