Glutathione-Disrupting Nanotherapeutics Potentiate Ferroptosis for Treating Luminal Androgen Receptor-Positive Triple-Negative Breast Cancer.
Jie LiYao WuYongping LiHongbo ZhuZhiwen ZhangYaping LiPublished in: ACS nano (2024)
The refractory luminal androgen receptor (LAR) subtype of triple-negative breast cancer (TNBC) patients is challenged by significant resistance to neoadjuvant chemotherapy and increased immunosuppression. Regarding the distinct upregulation of glutathione (GSH) and glutathione peroxidase 4 (GPX4) in LAR TNBC tumors, we herein designed a GSH-depleting phospholipid derivative (BPP) and propose a BPP-based nanotherapeutics of RSL-3 (GDNS), aiming to deplete intracellular GSH and repress GPX4 activity, thereby potentiating ferroptosis for treating LAR-subtype TNBC. GDNS treatment drastically downregulated the expression of GSH and GPX4, resulting in a 33.88-fold enhancement of lipid peroxidation and significant relief of immunosuppression in the 4T1 TNBC model. Moreover, GDNS and its combination with antibody against programed cell death protein 1 (antiPD-1) retarded tumor growth and produced 2.83-fold prolongation of survival in the LAR-positive TNBC model. Therefore, the GSH-disrupting GDNS represents an encouraging strategy to potentiate ferroptosis for treating refractory LAR-subtype TNBC.
Keyphrases
- cell death
- neoadjuvant chemotherapy
- fluorescent probe
- poor prognosis
- end stage renal disease
- cell cycle arrest
- ejection fraction
- locally advanced
- chronic kidney disease
- lymph node
- newly diagnosed
- squamous cell carcinoma
- cell proliferation
- sentinel lymph node
- fatty acid
- hydrogen peroxide
- early stage
- radiation therapy
- patient reported outcomes
- combination therapy
- patient reported