Harnessing disulfidptosis-ferroptosis synergy to potentiate radiotherapy in triple-negative breast cancer

Triple-negative breast cancer (TNBC) displays pronounced molecular heterogeneity and metastatic propensity, which correlates with its poor clinical prognosis. Crucially, radiotherapy (RT) resistance serves as a pivotal contributor to treatment failure and disease advancement in TNBC. To address this challenge, we developed BWFP, which is achieved by loading WZB117 and FIN56 onto bismuth-based metal organic framework with radiosensitization effect and surface modifying pH-responsive DSPE-PEOz. Under the acidic tumor microenvironment, BWFP controllably releases its payload: WZB117 suppresses glucose uptake through GLUT1 downregulation, thereby limiting NADPH production and inducing cystine accumulation alongside cysteine depletion, which concurrently triggers disulfidptosis and relieves ferroptosis resistance. Meanwhile, the released ferroptosis inducer FIN56 further amplifies ferroptosis by degrading GPX4. In addition to this, BWFP enhances RT efficacy through radiosensitization effects, consequently intensifying DNA damage. In a word, BWFP demonstrates robust anti-tumor activity in TNBC models by concomitantly inducing disulfidptosis and ferroptosis with synergized radiosensitization. Graphical abstract