Wang Huifang, Zhou Runhua, Xu Chengchao, Dai Lingyun, Hou Rui, Zheng Liuhai, Fu Chunjin, Shi Guangwei, Wang Jingwei, Li Yang, Cen Jinpeng, Xu Xiaolong, Yu Le, Li Yilei, Wang Jigang, Du Qingfeng, Li Zhijie
Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Centre for Geriatrics, Department of Nuclear Medicine, Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical CollegeJinan University), Shenzhen, Guangdong, 518020, China.
Post-doctoral Scientific Research Station of Basic Medicine, Jinan University, Guangzhou, 510632, China.
Adv Sci (Weinh). 2025 May;12(19):e2408086. doi: 10.1002/advs.202408086. Epub 2025 Mar 26.
The lack of targetable antigens poses a significant challenge in developing effective cancer-targeted therapies. Cell surface translocation of endoplasmic reticulum (ER) chaperones, such as glucose-regulated protein 78 (GRP78), during malignancy, drug resistance, and ER stress induced by therapies, offers a promising pan-cancer target. To target GRP78, nanobody C5, identified from a phage library and exhibiting high affinity for human and mouse GRP78, is utilized to develop the Pseudomonas exotoxin (PE) immunotoxin C5-PE38. C5-PE38 induced ER stress, apoptosis and immunogenic cell death in targeted cells and showed antitumor efficacy against colorectal cancer and melanoma models without obvious toxicity. Mechanistically, transcriptome profiling showed that C5-PE38 reshaped the tumor immune microenvironment with enhanced innate and adaptive immune response and response to interferon beta. Moreover, C5-PE38-induced cell death could trans-activate STING pathway in dendritic cells and macrophages, promoting CD8 T cell infiltration. It also sensitizes both primary and metastatic melanomas to anti-PD1 therapy, partly through STING activation. Overall, this study unveils a feasible GRP78 nanobody-directed therapy strategy for single or combinatorial cancer intervention. This work finds that C5-PE38-induced cell death stimulates STING-dependent cytosolic DNA release to promote antitumor immunity, a mechanism not previously reported for PE38, providing valuable insights for its clinical use.
缺乏可靶向的抗原是开发有效的癌症靶向疗法的重大挑战。在内质网（ER）伴侣蛋白（如葡萄糖调节蛋白78，GRP78）于恶性肿瘤、耐药性及治疗诱导的内质网应激期间发生细胞表面易位时，可提供一个有前景的泛癌靶点。为了靶向GRP78，从噬菌体文库中筛选出的对人和小鼠GRP78具有高亲和力的纳米抗体C5，被用于开发假单胞菌外毒素（PE）免疫毒素C5-PE38。C5-PE38在靶向细胞中诱导内质网应激、凋亡和免疫原性细胞死亡，并对结直肠癌和黑色素瘤模型显示出抗肿瘤疗效且无明显毒性。从机制上讲，转录组分析表明C5-PE38重塑了肿瘤免疫微环境，增强了固有免疫和适应性免疫反应以及对干扰素β的反应。此外，C5-PE38诱导的细胞死亡可在树突状细胞和巨噬细胞中转激活STING通路，促进CD8 T细胞浸润。它还使原发性和转移性黑色素瘤对抗PD1治疗敏感，部分是通过激活STING。总体而言，本研究揭示了一种可行的针对GRP78纳米抗体的治疗策略，用于单一或联合癌症干预。这项工作发现C5-PE38诱导的细胞死亡刺激STING依赖性胞质DNA释放以促进抗肿瘤免疫，这是此前未报道的PE38的机制，为其临床应用提供了有价值的见解。
