Journal Article

A covalent peptide-based lysosome-targeting protein degradation platform for cancer immunotherapy

Yang, Xin, Luo, Feiyu, Zhou, Xiuman, Wang, Mengfan, Li, Wanqiong, Su, Ye, Liu, Juan, He, Zhuoying, Gao, Yanfeng, Zeng, Wenxuan, Xiao, Youmei, Qian, Yuzhen, Chen, Guanyu, Niu, Xiaoshuang, Sui, Xinghua, Chen, Danhong

2025

Overview

The lysosome-targeting chimera (LYTAC) strategy provided a very powerful tool for the degradation of membrane proteins. However, the synthesis of LYTACs, antibody-small molecule conjugates, is challenging. The ability of antibody-based LYTACs to penetrate solid tumor is limited as well, especially to cross the blood-brain barrier (BBB). Here, we propose a covalent chimeric peptide-based targeted degradation platform (Pep-TACs) by introducing a long flexible aryl sulfonyl fluoride group, which allows proximity-enabled cross-linking upon binding with the protein of interest. The Pep-TACs platform facilitates the degradation of target proteins through the mechanism of recycling transferrin receptor (TFRC)-mediated lysosomal targeted endocytosis. Biological experiments demonstrate that covalent Pep-TACs can significantly degrade the expression of PD-L1 on tumor cells, dendritic cells and macrophages, especially under acidic conditions, and markedly enhance the function of T cells and tumor phagocytosis by macrophages. Furthermore, both in anti-PD-1-responsive and -resistant tumor models, the Pep-TACs exert significant anti-tumor immune response. It is noteworthy that Pep-TACs can cross the BBB and prolong the survival of mice with in situ brain tumor. As a proof-of-concept, this study introduces a modular TFRC-based covalent peptide degradation platform for the degradation of membrane protein, and especially for the immunotherapy of brain tumors. LYTAC strategies often face challenges in solid tumor penetration and synthesis. Here, the authors introduce Pep-TACs, a modular TFRC-based covalent peptide degradation platform that effectively degrades membrane protein PD-L1. This approach significantly suppresses both anti-PD-1-responsive and -resistant tumor growth, particularly in brain tumors.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/109 / 13/21 / 13/31 / 13/51 / 147/135 / 38/1 / 38/35 / 38/39 / 38/5 / 38/77 / 45 / 631/154/309/2420 / 631/45/611 / 639/638/92/611 / 64/60 / 692/699/67/1059 / 82/29 / 82/58 / 82/80 / 82/81 / 82/83 / Animals / Antibodies / B7-H1 Antigen - metabolism / Biodegradation / Blood-brain barrier / Blood-Brain Barrier - metabolism / Brain cancer / Brain Neoplasms - immunology / Brain Neoplasms - therapy / Brain tumors / Cancer immunotherapy / Cell Line, Tumor / Chemical synthesis / Chimeras / Covalence / Crosslinking / Degradation / Dendritic cells / Dendritic Cells - immunology / Dendritic Cells - metabolism / Endocytosis / Female / Humanities and Social Sciences / Humans / Immune response / Immune system / Immunotherapy / Immunotherapy - methods / Lymphocytes / Lymphocytes T / Lysosomes - metabolism / Macrophages / Macrophages - immunology / Macrophages - metabolism / Membrane proteins / Membranes / Mice / Mice, Inbred C57BL / multidisciplinary / Neoplasms - immunology / Neoplasms - therapy / PD-1 protein / PD-L1 protein / Penetration resistance / Peptides / Peptides - chemistry / Peptides - metabolism / Phagocytosis / Protein biosynthesis / Protein turnover / Proteins / Proteolysis / Receptors, Transferrin - metabolism / Science / Science (multidisciplinary) / Solid tumors / T-Lymphocytes - immunology / Transferrin / Tumor cells / Tumors