Abstract
Objective: Tumor cell radio-resistance and radiation-induced fibrosis of normal tissues hinder the efficacy of radiotherapy. Nintedanib, a promising therapeutic agent for radiation-induced pulmonary fibrosis and solid tumors, has yet to be investigated in combination with radiotherapy. This study aimed to evaluate the antitumor efficacy of nintedanib in conjunction with radiotherapy. Methods: Tumor-bearing models were utilized to assess the antitumor effects and safety of treatment with nintedanib and radiotherapy in vivo. Reactive oxygen species (ROS), lipid peroxidation assays, and transmission electron microscopy were used to determine the impact of the combined treatment strategy on tumor cell death. Overexpression plasmids and shRNA knockdown techniques were applied to explore and validate the underlying mechanisms. Results: The combination of nintedanib and radiotherapy demonstrated a potent antitumor effect in vivo. Nintedanib suppressed the SLC7A11-mediated GSH synthesis pathway by downregulating ATF4, the expression of which was elevated in response to radiation as an adaptive mechanism. Consequently, nintedanib combined with radiotherapy enhanced ferroptosis in tumor cells. Conclusions: These findings support the use of nintedanib in combination with radiotherapy as an effective, low-toxicity treatment strategy, highlighting the antitumor potential of ATF4-targeted agents.