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

  • J Med Chem. 2026 May 14;69(9):11312-11334. doi: 10.1021/acs.jmedchem.6c00477.
Guimei Li  1 ,  Juping Tang  1 ,  Lang Wang  2 ,  Meng Wang  2 ,  Yong Yang  2 ,  Zhikun Liu  2 ,  Hengshan Wang  1 ,  Xiaochao Huang  2
Affiliations
  • 1. Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guangxi 541004, China.
  • 2. Jiangsu Key Laboratory of Regional Specific Resource Pharmaceutical Transformation, Huaiyin Institute of Technology, Huai'an 223003, China.
PMID: 41992775 DOI: 10.1021/acs.jmedchem.6c00477
Abstract

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.

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