Unravelling T cell exhaustion through co-inhibitory receptors and its transformative role in cancer immunotherapy

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-05-25 DOI:10.1002/ctm2.70345

Simin Xiang, Sen Li, Junfen Xu

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Abstract

Persistent stimulation from cancer antigens leads to T lymphocytes (T cells) exhaustion, with up-regulated expression of co-inhibitory receptors, including programmed death-1 (PD-1), cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and mucin domain 3 (TIM-3) and T cell immunoreceptor with Ig and ITIM domains (TIGIT). These receptors collectively impair T cell function via distinct molecular pathways, contributing to immune evasion and cancer progression. This review highlights the therapeutic promise of immune checkpoint inhibitors (ICIs) in reversing T cell exhaustion while delving into the complex molecular processes and functional works of these important co-inhibitory receptors in tumourigenesis. Additionally, we examine the synergistic effects of combining ICIs with other therapeutic strategies, which can enhance anti-tumour efficacy. Finally, the clinical implications of bispecific antibodies are highlighted, representing a promising frontier in cancer immunotherapy, that could revolutionise treatment paradigms while improving patient outcomes.

Highlights

This review discusses five major co-inhibitory receptors (PD-1, CTLA-4, LAG-3, TIM-3 and TIGIT) and their related mechanisms of T cell exhaustion in the tumour environment.
We also discuss the clinical application of checkpoint inhibitors (ICIs) in cancer immunotherapy.
The potential of bispecific antibodies (BsAbs) in cancer immunotherapy is highlighted.

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通过共抑制受体揭示T细胞衰竭及其在癌症免疫治疗中的转化作用

肿瘤抗原的持续刺激导致T淋巴细胞（T细胞）耗竭，共抑制受体的表达上调，包括程序性死亡-1 （PD-1）、细胞毒性T淋巴细胞相关抗原-4 （CTLA-4）、淋巴细胞活化基因3 （LAG-3）、T细胞免疫球蛋白和黏液蛋白结构域3 （TIM-3）和具有Ig和ITIM结构域的T细胞免疫受体（TIGIT）。这些受体通过不同的分子途径共同损害T细胞功能，促进免疫逃避和癌症进展。这篇综述强调了免疫检查点抑制剂（ICIs）在逆转T细胞衰竭方面的治疗前景，同时深入研究了这些重要的共抑制受体在肿瘤发生中的复杂分子过程和功能作用。此外，我们研究了将ICIs与其他治疗策略联合使用的协同效应，这可以增强抗肿瘤疗效。最后，强调了双特异性抗体的临床意义，代表了癌症免疫治疗的一个有前途的前沿，它可以彻底改变治疗范式，同时改善患者的治疗效果。本文综述了5种主要的共抑制受体PD-1、CTLA-4、LAG-3、TIM-3和TIGIT及其在肿瘤环境中T细胞衰竭的相关机制。我们还讨论了检查点抑制剂（ICIs）在癌症免疫治疗中的临床应用。双特异性抗体（BsAbs）在癌症免疫治疗中的潜力被强调。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.