Xiao Dian, Dong Jingwen, Xie Fei, Feng Xun, Wang Jianfeng, Xu Xin, Tang Borui, Sun Cuicui, Wang Yuting, Zhong Wu, Deng Hongbin, Zhou Xinbo, Li Song
National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Nat Chem Biol. 2025 Jun 13. doi: 10.1038/s41589-025-01924-1.
Lysosome-targeting chimeras (LYTACs) represent a revolutionary targeted protein degradation technology. However, the advancement of LYTACs faces substantial challenges due to the limited diversity of lysosome-trafficking receptors. In this study, we identified folate receptor α (FRα) as a new class of lysosome-trafficking receptors capable of facilitating the degradation of membrane proteins. Leveraging a polyvalent crosslinking strategy, we developed FRα-targeting chimeras (FRTACs), including enhanced green fluorescent protein-targeting FR-Ctx and PD-L1-targeting FR-Atz. The optimized FRTACs demonstrated subnanomolar potency in eliminating cell-surface targets, with efficacy dependent on both FRα expression and lysosomal activity. Specifically, FR-Ctx inhibited cancer cell proliferation, while FR-Atz enhanced T cell-mediated cytotoxicity against tumor cells. FR-Atz exhibited robust PD-L1 degradation efficiency in vivo and elicited tumor-specific immune responses by reprogramming the tumor microenvironment from an immunosuppressive to an immunostimulatory state in both RM-1 and humanized B16F10 mouse models. These findings establish FRTACs as a promising platform for the design of tumor-targeting LYTACs.
溶酶体靶向嵌合体（LYTACs）是一种革命性的靶向蛋白质降解技术。然而，由于溶酶体运输受体的多样性有限，LYTACs的发展面临着重大挑战。在本研究中，我们鉴定出叶酸受体α（FRα）是一类能够促进膜蛋白降解的新型溶酶体运输受体。利用多价交联策略，我们开发了靶向FRα的嵌合体（FRTACs），包括靶向增强型绿色荧光蛋白的FR-Ctx和靶向程序性死亡配体1（PD-L1）的FR-Atz。优化后的FRTACs在消除细胞表面靶点方面表现出亚纳摩尔级别的效力，其疗效依赖于FRα的表达和溶酶体活性。具体而言，FR-Ctx抑制癌细胞增殖，而FR-Atz增强T细胞介导的对肿瘤细胞的细胞毒性。在RM-1和人源化B16F10小鼠模型中，FR-Atz在体内表现出强大的PD-L1降解效率，并通过将肿瘤微环境从免疫抑制状态重编程为免疫刺激状态引发肿瘤特异性免疫反应。这些发现确立了FRTACs作为设计肿瘤靶向LYTACs的一个有前景的平台。
