<p>Lung cancer remains a global health challenge, with a five-year survival rate of only 15–20%. This review focuses on the current landscape of combination therapies in lung cancer, emphasizing their molecular mechanisms. We explore novel combinations of ionizing radiation modalities (including X-rays, gamma rays, protons, and carbon ions) with small molecules such as checkpoint inhibitors, tyrosine kinase inhibitors, Anaplastic Lymphoma Kinase inhibitors, Poly (ADP-ribose) polymerase (PARP) inhibitors, and other drugs traditionally used in lung cancer treatments. Notably, certain types of lung cancer exhibit resistance to radiotherapy, and combination treatments are being employed not only to overcome this radioresistance by sensitizing these cells to radiation but also to enhance the overall efficacy of treatment. An important advantage of combination therapy is the potential to reduce the individual doses of drugs while maintaining the same therapeutic effect, which can minimize side effects. This review aims to provide a comprehensive overview of the current advancements in combination therapies for lung cancer, addressing both their potential and the challenges they present. By discussing these novel strategies, we seek to illuminate key areas for future research and development that could improve clinical outcomes and advance the treatment of lung cancer. Overall, combination therapies integrating ionizing radiation with targeted and immunomodulatory approaches hold significant promise for overcoming resistance and improving survival in lung cancer patients.</p> Graphical abstract <p></p>