FAP-targeted radionuclide therapy induces ferroptosis in cancer-associated fibroblasts via disrupting iron homeostasis and redox balance

Cancer-associated fibroblasts (CAFs) are crucial in tumor progression and treatment resistance. Fibroblast activation protein (FAP) is an important molecular target in nuclear medicine for cancer diagnosis and therapy. Through comprehensive bioinformatic analysis and experimental validation, FAP was identified as a potential regulator of ferroptosis in CAFs. In this study, we developed a targeted radionuclide therapy (TRT) using a novel radiopharmaceutical, 131 I-labeled FAP inhibitor ( 131 I-FAPi), to specifically target CAFs and induce ferroptosis. Mechanistically, 131 I-FAPi TRT triggered three synergistic pathways. First, β -radiation-mediated water radiolysis generated hydrated electrons (e aq - ), which drove the conversion of Fe 3+ to Fe 2+ , disrupting iron homeostasis. Second, β -radiation-mediated water radiolysis produced primary ROS, providing an oxidative stress source promoting lipid peroxidation. Third, 131 I-FAPi TRT suppressed the expression of key antioxidant proteins SLC7A11 and GPX4, weakening the antioxidant defenses of CAFs. Furthermore, the study demonstrated that the combination of 131 I-FAPi TRT with cold atmospheric plasma (CAP) treatment significantly enhanced ferroptosis through efficient Fenton reaction activation. This study revealed the mechanism of β -radionuclide therapy in modulating cellular redox status and iron metabolism and provided a rational basis for developing combination therapies, such as TRT with CAP, to overcome treatment resistance and improve cancer outcomes. 131 I-FAPi targeted radionuclide therapy triggered CAF ferroptosis via radiation-disrupted iron homeostasis, enhanced lipid peroxidation, and antioxidant system collapse, enhanced by CAP treatment.