Enhancing Ferroptosis-Mediated Radiosensitization <i>via</i> Synergistic Disulfidptosis Induction

Ferroptosis plays an important role in radiotherapy (RT), and the induction of ferroptosis can effectively sensitize radiotherapy. However, the therapeutic efficiency is always affected by ferroptosis resistance, especially SLC7A11 (Solute Carrier Family 7 Member 11)-cystine-cysteine-GSH (glutathione)-GPX4 (glutathione peroxidase 4) pathway-mediated resistance. In this study, tumor-microenvironment self-activated high-Z element-containing nanoferroptosis inducers, PEGylated Fe-Bi-SS metal-organic frameworks (FBSP MOFs), were developed to sensitize RT. Unexpectedly, ferroptosis-resistant SLC7A11 would be self-adaptively upregulated, leading to self-responsive ferroptosis resistance. Since the conversion from SLC7A11-transported cystine to cysteine is highly glucose-dependent, glucose oxidase (GOx) was incorporated in the MOFs, causing the depletion of NADPH (nicotinamide adenine dinucleotide phosphate) to terminate the conversion from cystine to cysteine, relieving the self-adaptive ferroptosis resistance. Excitingly, the accumulation of cystine would synergistically lead to disulfide stress and trigger disulfidptosis, making a new contribution to enhance therapeutic efficiency. Moreover, the hydrogen peroxide produced during glucose oxidation could also cascade-react with the Fenton reaction, therefore enhancing ferropotosis. Both <i>in vitro</i> and <i>in vivo</i> results suggested that therapeutic efficiency of ferroptosis-mediated radiosensitization could be enhanced benefiting from synergistic disulfidptosis induction, indicating that disulfidptosis might be an efficient strategy to relieve ferroptosis resistance and enhance RT efficiency.