肿瘤免疫治疗中对PD-1阻断的抵抗极大地限制了其临床应用。 T 细胞免疫球蛋白和粘蛋白结构域 3 (Tim-3) 是一种很有前途的免疫检查点靶标，可被 ADAM10/17 切割，在人体中产生其可溶形式 (sTim-3)，可能参与抗 PD-1 耐药性。在此，在非小细胞肺癌（NSCLC）和各种消化系统肿瘤中观察到血清 sTim-3 上调。值得注意的是，在接受抗 PD-1 治疗的非小细胞肺癌无反应患者和抗 PD-1 耐药胆管癌患者中，血清 sTim-3 进一步上调。此外，sTim-3 过表达可促进肿瘤进展，并在多种肿瘤小鼠模型中赋予抗 PD-1 耐药性。从机制上讲，sTim-3 通过癌胚抗原相关细胞粘附分子 1 (CEACAM-1) 诱导终末 T 细胞耗竭，并减弱 CD8 T 细胞对 PD-1 阻断的反应。此外，ADAM10 抑制剂 GI254023X 可阻断 sTim-3 的产生，减少 Tim-3 人源化小鼠的肿瘤进展，并逆转人肿瘤浸润淋巴细胞 (TIL) 中的抗 PD-1 耐药性。总体而言，人类 sTim-3 在肿瘤免疫治疗中具有巨大的预测和治疗潜力。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Resistance to PD-1 blockade in onco-immunotherapy greatly limits its clinical application. T cell immunoglobulin and mucin domain containing-3 (Tim-3), a promising immune checkpoint target, is cleaved by ADAM10/17 to produce its soluble form (sTim-3) in humans, potentially becoming involved in anti-PD-1 resistance. Herein, serum sTim-3 upregulation was observed in non-small cell lung cancer (NSCLC) and various digestive tumors. Notably, serum sTim-3 is further upregulated in non-responding patients undergoing anti-PD-1 therapy for NSCLC and anti-PD-1-resistant cholangiocarcinoma patients. Furthermore, sTim-3 overexpression facilitates tumor progression and confers anti-PD-1 resistance in multiple tumor mouse models. Mechanistically, sTim-3 induces terminal T cell exhaustion and attenuates CD8+ T cell response to PD-1 blockade through carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1). Moreover, the ADAM10 inhibitor GI254023X, which blocks sTim-3 production, reduces tumor progression in Tim-3 humanized mice and reverses anti-PD-1 resistance in human tumor-infiltrating lymphocytes (TILs). Overall, human sTim-3 holds great predictive and therapeutic potential in onco-immunotherapy.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.