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.