Zhu Xiaokang, Xie Li, Liao Qing, Tian Jinming, Peng Jinlin, Chen Zhu, Song Erqun, Song Yang
Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of Education, College of Pharmaceutical Sciences, Southwest University, 2 Tiansheng Rd, Beibei District, Chongqing, 400715, China.
Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of Education, College of Pharmaceutical Sciences, Southwest University, 2 Tiansheng Rd, Beibei District, Chongqing, 400715, China.
Acta Biomater. 2025 Aug 8. doi: 10.1016/j.actbio.2025.08.014.
Ferrotherapy has risen as a promising therapeutic approach for triple-negative breast cancer (TNBC); however, its potency is frequently compromised due to tumor cells' ability to evade ferroptosis via various resistance pathways and insufficient immunogenicity. To overcome these limitations, we have engineered a calcium phosphate-mineralized ferroptosis inducer nanoplatform, termed Lf-PEG-CaP@iFSP1-Brequinar-Erastin-Fe-TA (LP-CaP@iBEFT), designed to augment ferroptosis by simultaneously targeting three key pathways: glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), and dihydroorotate dehydrogenase (DHODH). Once internalized and reached the acidic tumor microenvironment (TME), the nanoplatform discharges its therapeutic payloads, comprising inhibitors of FSP1 (iFSP), brequinar, erastin, and iron ions. The first three components were tailored to inhibit key pathways to ferroptosis, while the released iron ions initiate ferroptosis by catalyzing the generation of reactive oxygen species (ROS) via Fenton reactions. The calcium phosphate-mineralized ferroptosis inducer nanoplatform promotes the maturation of DC cells, enhances the infiltration of T cells and releases immunity-related factors, thereby altering the immunosuppressive microenvironment. In conjunction with anti-PD-L1 therapy, LP-CaP@iBEFT boosts T lymphocyte-mediated immune infiltration, thereby amplifying the anti-tumor response and offering a therapeutic approach for TNBC. STATEMENT OF SIGNIFICANCE: We developed an acid-responsive nanoplatform that specifically targets tumor cells that overexpress lactoferrin receptors. This nanoplatform degrades within the acidic tumor environment to release the payload components iFSP1, brequinar, erastin, and Fe, which collectively inhibit three pathways of ferroptosis. This approach effectively dismantles the "triple defense" mechanism that tumor cells employ to resist ferroptosis. In addition, this nanoplatform synergizes with anti-PD-L1 immune checkpoint blockade, enhancing the T cell-mediated destruction of tumor cells.
铁疗法已成为一种有前景的三阴性乳腺癌（TNBC）治疗方法；然而，由于肿瘤细胞能够通过各种抗性途径逃避铁死亡以及免疫原性不足，其效力常常受到影响。为了克服这些限制，我们构建了一种磷酸钙矿化的铁死亡诱导剂纳米平台，称为Lf-PEG-CaP@iFSP1-布雷喹那-艾拉司丁-铁-TA（LP-CaP@iBEFT），旨在通过同时靶向三个关键途径来增强铁死亡：谷胱甘肽过氧化物酶4（GPX4）、铁死亡抑制蛋白1（FSP1）和二氢乳清酸脱氢酶（DHODH）。一旦纳米平台内化并到达酸性肿瘤微环境（TME），它就会释放其治疗载荷，包括FSP1抑制剂（iFSP）、布雷喹那、艾拉司丁和铁离子。前三个成分经过定制以抑制铁死亡的关键途径，而释放的铁离子通过芬顿反应催化活性氧（ROS）的产生来引发铁死亡。磷酸钙矿化的铁死亡诱导剂纳米平台促进树突状细胞（DC）成熟，增强T细胞浸润并释放免疫相关因子，从而改变免疫抑制微环境。与抗PD-L1疗法联合使用时，LP-CaP@iBEFT增强T淋巴细胞介导的免疫浸润，从而放大抗肿瘤反应并为TNBC提供一种治疗方法。重要意义声明：我们开发了一种酸响应性纳米平台，该平台特异性靶向过表达乳铁蛋白受体的肿瘤细胞。这种纳米平台在酸性肿瘤环境中降解以释放载荷成分iFSP1、布雷喹那、艾拉司丁和铁，它们共同抑制铁死亡的三个途径。这种方法有效地打破了肿瘤细胞用于抵抗铁死亡的“三重防御”机制。此外，这种纳米平台与抗PD-L1免疫检查点阻断协同作用，增强T细胞介导的肿瘤细胞破坏。
