Wang Jie, Zhang Zilong, Zhuo Yan, Zhang Zhuan, Chen Rongrong, Liang Li, Jiang Xiaohe, Nie Di, Liu Chang, Zou Zhiwen, Li Xiang, Li Jiaxin, Wang Bingqi, Wang Rui, Gan Yong, Yu Miaorong
School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Acta Pharm Sin B. 2024 Aug;14(8):3643-3660. doi: 10.1016/j.apsb.2024.04.010. Epub 2024 Apr 15.
The prospect of employing chemoimmunotherapy targeted towards the endoplasmic reticulum (ER) presents an opportunity to amplify the synergistic effects of chemotherapy and immunotherapy. In this study, we initially validated celastrol (CEL) as an inducer of immunogenic cell death (ICD) by promoting ER stress and autophagy in colorectal cancer (CRC) cells. Subsequently, an ER-targeted strategy was posited, involving the codelivery of CEL with PD-L1 small interfering RNAs (siRNA) using KDEL peptide-modified exosomes derived from milk (KME), to enhance chemoimmunotherapy outcomes. Our findings demonstrate the efficient transportation of KME to the ER the Golgi-to-ER pathway. Compared to their non-targeting counterparts, KME exhibited a significant augmentation of the CEL-induced ICD effect. Additionally, it facilitated the release of danger signaling molecules (DAMPs), thereby stimulating the antigen-presenting function of dendritic cells and promoting the infiltration of T cells into the tumor. Concurrently, the ER-targeted delivery of PD-L1 siRNA resulted in the downregulation of both intracellular and membrane PD-L1 protein expression, consequently fostering the proliferation and activity of CD8 T cells. Ultimately, the ER-targeted formulation exhibited enhanced anti-tumor efficacy and provoked anti-tumor immune responses against orthotopic colorectal tumors . Collectively, a robust ER-targeted delivery strategy provides an encouraging approach for achieving potent cancer chemoimmunotherapy.
采用针对内质网（ER）的化学免疫疗法有望增强化疗和免疫疗法的协同效应。在本研究中，我们首先通过促进结直肠癌（CRC）细胞的内质网应激和自噬，验证了雷公藤红素（CEL）作为免疫原性细胞死亡（ICD）诱导剂的作用。随后，提出了一种内质网靶向策略，即使用源自牛奶的KDEL肽修饰外泌体（KME）将CEL与程序性死亡配体1小干扰RNA（siRNA）共同递送，以提高化学免疫治疗效果。我们的研究结果表明，KME通过高尔基体到内质网途径有效地运输到内质网。与非靶向对应物相比，KME显著增强了CEL诱导的ICD效应。此外，它促进了危险信号分子（DAMPs）的释放，从而刺激树突状细胞的抗原呈递功能，并促进T细胞浸润到肿瘤中。同时，内质网靶向递送PD-L1 siRNA导致细胞内和膜上PD-L1蛋白表达下调，从而促进CD8 T细胞的增殖和活性。最终，内质网靶向制剂表现出增强的抗肿瘤疗效，并引发针对原位结直肠癌肿瘤的抗肿瘤免疫反应。总的来说，一种强大的内质网靶向递送策略为实现有效的癌症化学免疫治疗提供了一种令人鼓舞的方法。
