Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291, Daehak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea.
ACS Appl Bio Mater. 2023 Dec 18;6(12):5290-5300. doi: 10.1021/acsabm.3c00581. Epub 2023 Dec 3.
Immunogenic cell death (ICD) has emerged as a promising approach to cancer immunotherapy. During ICD, cancer cell death and the release of damage-associated molecular pattern (DAMP) signals occur simultaneously. Increased production of reactive oxygen species (ROS) and severe endoplasmic reticulum stress are necessary for enhanced ICD. Furthermore, the levels of ROS and reduced glutathione (GSH) are involved in various cell death mechanisms. The thiazole ring structure has gained considerable interest as a functional moiety for anticancer agents. This study designed and synthesized a positively charged cell-penetrating polypeptide with a thiazole functional moiety (NS). The NS internalizes into the cancer cells through direct penetration and endo-lysosomal escape. The NS induces mitochondrial depolarization and ER stress in a concentration-dependent manner, leading to a significant ROS production and GSH depletion. Consequently, the ICD of cancer cells is activated, resulting in the release of DAMP signals. Furthermore, NS causes a shift in the cell death pathway from apoptosis to necroptosis as the concentration increases. In this study, we confirmed the possibility of NS as a promising ICD inducer that can be used while varying the concentration according to the cancer type.
免疫原性细胞死亡 (ICD) 已成为癌症免疫治疗的一种有前途的方法。在 ICD 期间，癌细胞死亡和损伤相关分子模式 (DAMP) 信号的释放同时发生。增加活性氧物种 (ROS) 的产生和严重的内质网应激是增强 ICD 的必要条件。此外，ROS 和还原型谷胱甘肽 (GSH) 的水平参与了各种细胞死亡机制。噻唑环结构作为抗癌药物的功能部分引起了相当大的关注。本研究设计并合成了一种带有噻唑功能部分的带正电荷的细胞穿透多肽 (NS)。NS 通过直接穿透和内体-溶酶体逃逸进入癌细胞。NS 以浓度依赖的方式诱导线粒体去极化和内质网应激，导致显著的 ROS 产生和 GSH 耗竭。因此，激活了癌细胞的 ICD，导致 DAMP 信号的释放。此外，随着浓度的增加，NS 导致细胞死亡途径从凋亡向坏死转变。在这项研究中，我们证实了 NS 作为一种有前途的 ICD 诱导剂的可能性，根据癌症类型，可以改变浓度来使用。
