Simultaneous Induction of Ferroptosis and Immunogenic Cell Death by TrxR-Targeted Pt(IV) Prodrugs for Chemoimmunotherapy of Triple-Negative Breast Cancer.

Thioredoxin reductase (TrxR) serves as a therapeutic target for triple-negative breast cancer (TNBC) treatment owing to its overexpression in TNBC cells. Herein, a series of Pt(IV) prodrugs targeting both TrxR and DNA were designed and synthesized. The superior complex 6b demonstrated remarkable activity against both cisplatin-sensitive and -resistant TNBC cells and effectively inhibited TrxR1 both in vitro and in vivo. Moreover, complex 6b significantly induced ferroptosis through glutathione depletion, the accumulation of intracellular lipid peroxidation, and the deactivation of glutathione peroxidase 4, respectively. Notably, complex 6b induced an excessive accumulation of intracellular reactive oxygen species to trigger endoplasmic reticulum (ER) stress and subsequently induce immunogenic cell death. Overall, this study presents an innovative strategy for enhancing cisplatin sensitivity and overcoming cisplatin resistance in TNBC through the use of dual-targeted TrxR and DNA Pt(IV) prodrugs, thereby offering a new approach to treating TNBC.