同种异体细胞疗法的免疫排斥仍然是免疫肿瘤学和再生医学的一个主要问题。迄今为止，与自体替代品相比，同种异体细胞产品的持久性和功效较差。低免疫细胞的工程化可以极大地提高其治疗效果。我们提出了一类新型激动性免疫检查点接合剂，可保护人类白细胞抗原（HLA）耗尽的诱导多能干细胞衍生内皮细胞（iEC）免受先天免疫细胞的侵害。对其抑制性受体 TIM3 和 SIRPα 具有激动功能的接合器可有效保护工程 iEC 免受自然杀伤 (NK) 细胞和巨噬细胞的杀伤。 SIRPα 接合器可以与截短的 CD64 结合，产生完全免疫逃避的 iEC，能够逃避同种异体细胞和免疫球蛋白 G (IgG) 抗体介导的排斥反应。合成免疫检查点接合剂具有很高的靶点特异性，并且在工程细胞中缺乏逆行信号传导。这种模块化设计允许利用更多的抑制性免疫途径来逃避免疫，并可能有助于同种异体细胞疗法的进步。版权所有 © 2023 作者。由爱思唯尔公司出版。保留所有权利。

Immune rejection of allogeneic cell therapeutics remains a major problem for immuno-oncology and regenerative medicine. Allogeneic cell products so far have inferior persistence and efficacy when compared with autologous alternatives. Engineering of hypoimmune cells may greatly improve their therapeutic benefit. We present a new class of agonistic immune checkpoint engagers that protect human leukocyte antigen (HLA)-depleted induced pluripotent stem cell-derived endothelial cells (iECs) from innate immune cells. Engagers with agonistic functionality to their inhibitory receptors TIM3 and SIRPα effectively protect engineered iECs from natural killer (NK) cell and macrophage killing. The SIRPα engager can be combined with truncated CD64 to generate fully immune evasive iECs capable of escaping allogeneic cellular and immunoglobulin G (IgG) antibody-mediated rejection. Synthetic immune checkpoint engagers have high target specificity and lack retrograde signaling in the engineered cells. This modular design allows for the exploitation of more inhibitory immune pathways for immune evasion and could contribute to the advancement of allogeneic cell therapeutics.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.