全能的
肿瘤微环境
癌症研究
免疫系统
肽
免疫检查点
封锁
免疫疗法
细胞生物学
生物
免疫学
受体
生物化学
细胞分化
基因
作者
Limin Zhang,Zhenqi Jiang,Xi Yang,Yixia Qian,Minxuan Wang,Shang Yin Wu,Lingyun Li,Fu Jia,Zihua Wang,Zhiyuan Hu,Minzhi Zhao,Xiaoying Tang,Gang Li,Haitao Shang,Xiaoyuan Chen,Weizhi Wang
标识
DOI:10.1002/adma.202207330
摘要
Immune checkpoint blockade combined with reversal of the immunosuppressive tumor microenvironment (TME) can dramatically enhance anti-tumor immunity, which can be achieved by using multiple-agent therapy. However, the optimal dose and order of administration of different agents remain elusive. To address this dilemma, multiple agents are often grafted together to construct "all-in-one" totipotent drugs, but this usually comes at the cost of a lack of synergy between the agents. Herein, by comprehensively analyzing the conserved sites of the immune checkpoint and TME drug targets, peptide secondary structures, assembly properties, and other physicochemical properties, a high-content peptide library is designed. By using the "3D-molecular-evolution" screening strategy, an efficient and totipotent "all-in-one" peptide (TAP) is obtained, which possesses the abilities of self-assembling, blocking the PD-1/PD-L1 axis, inhibiting Rbm38-eIF4E complex formation, and activating p53. It is shown that in mice treated with TAP, with either subcutaneous tumors or patient-derived xenografts, PD-L1 is blocked, with increased activation of both T and NK cells whilst reversing the immunosuppressive TME. Moreover, TAP can mitigate tumor activity and suppress tumor growth, showing superior therapeutic effect over antibody-based drugs.
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