Aftabi, SajjadBarzegar Behrooz, AmirCordani, MarcoRahiman, NiloufarSadeghdoust, MohammadaminAligolighasemabadi, FarnazPistorius, StephenAlavizadeh, Seyedeh HodaTaefehshokr, NimaGhavami, Saeid2025-02-192025-02-192024Aftabi, S., Barzegar Behrooz, A., Cordani, M., Rahiman, N., Sadeghdoust, M., Aligolighasemabadi, F., Pistorius, S., Alavizadeh, S.H., Taefehshokr, N. and Ghavami, S. (2025), Therapeutic targeting of TGF-β in lung cancer. FEBS J. https://doi.org/10.1111/febs.172341742-464X10.1111/febs.17234https://hdl.handle.net/20.500.14352/118218MC was supported by grant RYC2021-031003I funded by MICIU/AEI/10.13039/501100011033 and by European Union NextGenerationEU/PRTR.Transforming growth factor-β (TGF-β) plays a complex role in lung cancer pathophysiology, initially acting as a tumor suppressor by inhibiting early-stage tumor growth. However, its role evolves in the advanced stages of the disease, where it contributes to tumor progression not by directly promoting cell proliferation but by enhancing epithelial–mesenchymal transition (EMT) and creating a conducive tumor microenvironment. While EMT is typically associated with enhanced migratory and invasive capabilities rather than proliferation per se, TGF-β's influence on this process facilitates the complex dynamics of tumor metastasis. Additionally, TGF-β impacts the tumor microenvironment by interacting with immune cells, a process influenced by genetic and epigenetic changes within tumor cells. This interaction highlights its role in immune evasion and chemoresistance, further complicating lung cancer therapy. This review provides a critical overview of recent findings on TGF-β's involvement in lung cancer, its contribution to chemoresistance, and its modulation of the immune response. Despite the considerable challenges encountered in clinical trials and the development of new treatments targeting the TGF-β pathway, this review highlights the necessity for continued, in-depth investigation into the roles of TGF-β. A deeper comprehension of these roles may lead to novel, targeted therapies for lung cancer. Despite the intricate behavior of TGF-β signaling in tumors and previous challenges, further research could yield innovative treatment strategies.spaAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/journal article1742-4658https://doi.org/10.1111/febs.17234https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.17234open access612.433.65612.37615.37616-006.04ChemoresistanceEpithelial–mesenchymal transitionImmunotherapyLung cancerTransforming growth factor-βBioquímica (Biología)OncologíaFisiologíaInmunología2403 Bioquímica3207.13 Oncología2411 Fisiología Humana2412 Inmunología