Sha Xuan, Wang Chuanbing, Liu Yang, Zhong Nan, Lu Yishi, Zhang Qi, Lu Shangyu, He Doudou, Jin Yingying, Tang Yuxia, Wang Shouju
Laboratory of Molecular Imaging, Department of Radiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
Department of Ultrasound, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
J Nanobiotechnology. 2025 Mar 19;23(1):224. doi: 10.1186/s12951-025-03307-z.
Inducing ferroptotic cell death has been recognized as a promising approach in cancer therapy. However, ferroptosis can provoke tumor infiltration by myeloid-derived suppressor cells (MDSCs) through HMGB1 secretion, causing a tumor suppressive immune response. On the other hand, ferroptosis also occurs the immune cells due to its non-selective properties, which can compromise anti-tumor immunity. To address these challenges, a two-pronged approach is proposed, encompassing selectively triggered ferroptosis in tumor cells and HMGB1 blockade, aimed at eliciting systemic anti-tumor immunity and alleviating immunosuppression. Herein, GSH-specific driven nanoplatform is composed of uniform FeOOH nanospindles coated with tetrasulfide bond-bridged mesoporous organosilica (DMOS) shell, and loaded with the HMGB1 inhibitor, glycyrrhizic acid (GA). This nanoplatform is endowed with high glutathione (GSH) depletion efficiency and exhibits highly efficient Fe and ROS generation capacity, which promotes the accumulation of LPO and subsequently induces ferroptosis. Concurrently, the inhibition of HMGB1 release counteracts the immunosuppressive effects within the tumor microenvironment. This innovative nanoplatform effectively suppresses the growth of 4T1 tumors and notably enhancing the therapeutic outcomes of immune checkpoint blockade across experimental data. The collective findings indicate its potential as a reliable therapeutic strategy for boosting ferroptosis-mediated tumor immunity with favorable safety profiles.
诱导铁死亡性细胞死亡已被认为是癌症治疗中一种有前景的方法。然而，铁死亡可通过高迁移率族蛋白B1（HMGB1）的分泌引发骨髓来源的抑制性细胞（MDSC）浸润肿瘤，从而引起肿瘤抑制性免疫反应。另一方面，由于铁死亡具有非选择性，免疫细胞也会发生铁死亡，这可能会损害抗肿瘤免疫力。为应对这些挑战，提出了一种双管齐下的方法，包括在肿瘤细胞中选择性触发铁死亡和阻断HMGB1，旨在引发全身抗肿瘤免疫并减轻免疫抑制。在此，谷胱甘肽（GSH）特异性驱动的纳米平台由包裹有四硫键桥连介孔有机硅（DMOS）壳的均匀FeOOH纳米纺锤体组成，并负载有HMGB1抑制剂甘草酸（GA）。该纳米平台具有高谷胱甘肽消耗效率，并表现出高效的铁和活性氧生成能力，可促进脂质过氧化（LPO）的积累，随后诱导铁死亡。同时，对HMGB1释放的抑制可抵消肿瘤微环境中的免疫抑制作用。这一创新的纳米平台有效地抑制了4T1肿瘤的生长，并在实验数据中显著提高了免疫检查点阻断的治疗效果。这些研究结果共同表明，它有潜力成为一种可靠的治疗策略，以增强铁死亡介导的肿瘤免疫，且具有良好的安全性。
