Self-assembled flavonoid-Pt(IV) prodrug inhibits tumor growth and metastasis via synergistic induction of DNA damage and ferroptosis-mediated immunogenic cell death

Triple-negative breast cancer (TNBC) is an aggressive type of cancer with high metastatic potential and poor clinical outcomes. Although cisplatin remains a widely used first-line therapeutic agent, its lack of tumor selectivity and its propensity to induce severe systemic toxicity severely compromise its real-world efficacy. This study designed and synthesized a novel self-assembled flavonoid-Pt(IV) prodrug (FLP) as a multimodal therapeutic against TNBC. FLP spontaneously assembled into uniform nanospheres with a hydrodynamic diameter of 150 nm, significantly enhancing cellular uptake and tumor-targeted accumulation. FLP exhibited potent cytotoxicity with IC 50 values ranging from 3.17 to 15.90 µM, substantially outperforming DFLP and cisplatin. Upon cellular internalization, reduction of the Pt(IV) scaffold consumed intracellular glutathione (GSH), directly disrupting redox homeostasis. This GSH depletion led to the inactivation of glutathione peroxidase 4 and triggered lipid peroxidation cascades, inducing ferroptosis. Concurrently, lipid peroxidation products and intracellular components released during ferroptosis served as damage-associated molecular patterns, activating immunogenic cell death (ICD). The flavonoid moiety further amplified oxidative stress, synergizing with the GSH-depleting property of the Pt(IV) scaffold. In vivo studies in a 4T1 orthotopic breast tumor model revealed that FLP achieved a tumor growth inhibition rate of 65.93%, significantly higher than that of cisplatin (49.63%), while effectively suppressing lung metastasis. In conclusion, this work presents a carrier-free Pt(IV) nanoassembly that integrates chemotherapy with ferroptosis-associated immunogenic responses, highlighting a nanoscale strategy for enhancing platinum-based therapy in TNBC.