嵌合抗原受体 T (CAR-T) 细胞疗法作为过继细胞疗法 (ACT) 的一种形式，在癌症治疗中显示出巨大的前景，FDA 批准的针对 CD19 或 B 细胞成熟抗原 (BCMA) 的 CAR-T 细胞疗法证明了这一点用于血液系统恶性肿瘤，尽管实体瘤的结果中等。然而，尽管取得了这些进步，CAR-T 疗法的疗效常常受到 T 细胞耗竭的影响，这种现象阻碍了 CAR-T 细胞的持久性和效应功能，导致接受治疗的患者的复发率高达 75%用于治疗血液恶性肿瘤的 CD19 或 CD22 CAR-T 细胞。克服 CAR-T 耗尽的策略采用最先进的基因组工程工具和单细胞测序技术。在这篇综述中，我们全面了解了 T 细胞耗竭的最新机制见解及其对当前优化 CAR-T 细胞疗法的影响。这些见解与最近临床试验中对基于 CAR-T 的产品进行基准测试所吸取的经验教训相结合，旨在解决 T 细胞耗竭带来的挑战，并有可能为开发定制的下一代癌症治疗方法奠定基础。© 2024作者。

Chimeric antigen receptor T (CAR-T) cell therapy as a form of adoptive cell therapy (ACT) has shown significant promise in cancer treatment, demonstrated by the FDA-approved CAR-T cell therapies targeting CD19 or B cell maturation antigen (BCMA) for hematological malignancies, albeit with moderate outcomes in solid tumors. However, despite these advancements, the efficacy of CAR-T therapy is often compromised by T cell exhaustion, a phenomenon that impedes the persistence and effector function of CAR-T cells, leading to a relapse rate of up to 75% in patients treated with CD19 or CD22 CAR-T cells for hematological malignancies. Strategies to overcome CAR-T exhaustion employ state-of-the-art genomic engineering tools and single-cell sequencing technologies. In this review, we provide a comprehensive understanding of the latest mechanistic insights into T cell exhaustion and their implications for the current efforts to optimize CAR-T cell therapy. These insights, combined with lessons learned from benchmarking CAR-T based products in recent clinical trials, aim to address the challenges posed by T cell exhaustion, potentially setting the stage for the development of tailored next-generation approaches to cancer treatment.© 2024 The Authors.