A new oxaliplatin(IV) prodrug inducing ferroptosis through a triple-pathway mechanism and activating anti-cancer immunity

Ferroptosis inducers exhibit great potential as anticancer drugs but face two key challenges: (1) non-selective toxicity toward both tumor and immune cells may suppress antitumor immunity; (2) tumor resistance driven by antioxidant defense mechanisms or iron metabolism regulation reduces therapeutic efficacy. To address these issues, herein, a new oxaliplatin(IV) prodrug FAOP by coupling artesunate (ART) and (3-carboxypropionyl) ferrocene (ferrocene fragments) was rationally designed. FAOP could release oxaliplatin (OP), ART and ferrocene fragments, exerting a synergistic anti-cancer effect. Firstly, ferrocene fragments would induce ferroptosis by catalyzing Fenton reaction to generate hydroxyl radicals (·OH), causing lipid peroxidation. Secondly, ART inhibited GPX4 by reducing glutathione (GSH) levels and generating reactive oxygen species (ROS), thereby disrupting the redox balance and further sensitizing cells to ferroptosis. Lastly, OP could induce apoptosis while synergizing with intracellular ROS, resulting in enhanced immunogenic cell death (ICD) and activating both innate and adaptive immunity. The immune effector-activated CD8⁺ T cells produced IFN-γ, which inhibited the cystine transport by tumor cells, further impaired GPX4 activation and sensitized ferroptosis. The mutual reinforcement strategy of ICD and ferroptosis mediated by FAOP could overcome the limitations of traditional chemotherapy and reverse immunosuppression caused by ferroptosis inducers, offering a novel idea for designing ferroptosis inducers.