Ye Pingting, Wang Chunhui, Wen Yixuan, Fang Kang, Li Qi, Zhang Xin, Yang Jingxian, Li Ruihao, Chen Mengyao, Tong Xiaohan, Shi Shuo, Dong Chunyan
Department of Oncology, Shanghai East Hospital, School of Medicine, Shanghai Key Laboratory of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, Shanghai, 200120, China.
Department of Oncology, Shanghai East Hospital, School of Medicine, Shanghai Key Laboratory of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, Shanghai, 200120, China.
Biomaterials. 2025 Apr;315:122960. doi: 10.1016/j.biomaterials.2024.122960. Epub 2024 Nov 12.
Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer due to poor immunogenicity and limited immune cell infiltration, efficient therapeutics are still deficiency. Ferroptosis, a reactive oxygen species (ROS)-reliant cell death, can enhance cellular immunogenicity and then active immune system. To sustain a long-term "hot" tumour immune microenvironment (TIME), an immune-modulator is indispensable. Metformin (MET), a commonly used oral drug for type 2 diabetes, has played a vital role in fostering an immunostimulatory environment. Herein, we confirm the TIME can be remodeled by MET and further promotes ferroptosis via upregulating cellular concentration of l-Glutamine. In light of this, we have design a self-assembled MET-loaded Fe-doped polydopamine nanoparticle (Fe-PDA-MET NP) that can disorder the cellular redox homeostasis and induce robust ferroptosis under 808 nm irradiation, resulting in a strong immune response. Based on the function of MET, there is a marked increase in the infiltration of activated CD8 T cells and NK cells, which subsequently augments ferroptosis to a greater extent. Taken together, Fe-PDA-MET NPs activate a ferroptotic positive-feedback loop for effectively control TNBC progression, which offers a promising therapeutic modality to enhance the immunogenicity and reshape the TIME.
三阴性乳腺癌（TNBC）是一种侵袭性特别强的乳腺癌亚型，因其免疫原性差且免疫细胞浸润有限，目前仍缺乏有效的治疗方法。铁死亡是一种依赖活性氧（ROS）的细胞死亡方式，可增强细胞免疫原性，进而激活免疫系统。为了维持长期的“热”肿瘤免疫微环境（TIME），免疫调节剂不可或缺。二甲双胍（MET）是一种常用的2型糖尿病口服药物，在营造免疫刺激环境方面发挥了重要作用。在此，我们证实MET可重塑TIME，并通过上调细胞内L-谷氨酰胺浓度进一步促进铁死亡。鉴于此，我们设计了一种自组装的载MET铁掺杂聚多巴胺纳米颗粒（Fe-PDA-MET NP），其可破坏细胞氧化还原稳态，并在808 nm光照下诱导强烈的铁死亡，从而引发强烈的免疫反应。基于MET的功能，活化的CD8 T细胞和NK细胞浸润显著增加，随后进一步增强铁死亡。综上所述，Fe-PDA-MET NPs激活了一个铁死亡正反馈回路，以有效控制TNBC进展，这为增强免疫原性和重塑TIME提供了一种有前景的治疗方式。
