Abstract

Triple-negative breast cancer (TNBC) remains a formidable clinical challenge due to its aggressive phenotype and limited therapeutic options. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, is evolving as a highly promising approach to combat TNBC. However, tumor cells deploy redundant ferroptosis defense systems including glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH) systems to evade this lethal process. Here, doxorubicin (DOX) and teriflunomide (Tfm) were used as therapeutic building blocks for the self-assembly of tumor-targeting, excipient-free nanoassemblies (DoT) that enhance ferroptosis induction in TNBC. After being trapped in cancer cells, the FDA-approved antitumor drug DOX could not only disrupt the GPX4 defense system by inhibiting Nrf2 but also ignite an intracellular reactive oxygen species storm to unleash a lipid peroxidation spark. Simultaneously, Tfm further devastated the intracellular ferroptosis defense system by suppressing DHODH and crippling the radical-trapping antioxidant capacity, thus evoking robust ferroptotic cell death in TNBC cells. The work presents a synergistic co-disruption strategy against dual ferroptosis defense systems, exhibiting significant potential for clinical applications.