Regulatory T cells (Tregs) are fundamental to maintaining immune homeostasis by inhibiting immune responses to self-antigens and preventing the excessive activation of the immune system. Their functions extend beyond immune surveillance and subpopulations of tissue-resident Treg cells can also facilitate tissue repair and homeostasis. The unique ability to regulate aberrant immune responses has generated the concept of harnessing Tregs as a new cellular immunotherapy approach for reshaping undesired immune reactions in autoimmune diseases and allo-responses in transplantation to ultimately re-establish tolerance. However, a number of issues limit the broad clinical applicability of Treg adoptive immunotherapy, including the lack of antigen specificity, heterogeneity within the Treg population, poor persistence, functional Treg impairment in disease states, and in vivo plasticity that results in the loss of suppressive function. Although the early-phase clinical trials of Treg cell therapy have shown the feasibility and tolerability of the approach in several conditions, its efficacy has remained questionable. Leveraging the smart tools and platforms that have been successfully developed for primary T cell engineering in cancer, the field has now shifted towards “next-generation” adoptive Treg immunotherapy, where genetically modified Treg products with improved characteristics are being generated, as regards antigen specificity, function, persistence, and immunogenicity. Here, we review the state of the art on Treg adoptive immunotherapy and progress beyond it, while critically evaluating the hurdles and opportunities towards the materialization of Tregs as a living drug therapy for various inflammation states and the broad clinical translation of Treg therapeutics.
调节性T细胞（Tregs）通过抑制对自身抗原的免疫反应并防止免疫系统过度激活，对维持免疫稳态至关重要。其功能不仅限于免疫监视，组织驻留性Treg细胞亚群还能促进组织修复与稳态维持。这种调节异常免疫反应的独特能力催生了利用Tregs作为新型细胞免疫疗法的理念，旨在重塑自身免疫性疾病中不良免疫反应及移植中的同种异体反应，最终重建免疫耐受。然而，多种因素限制了Treg过继免疫疗法的广泛临床应用，包括抗原特异性缺失、Treg群体异质性、体内持久性差、疾病状态下功能性Treg受损，以及导致抑制功能丧失的体内可塑性问题。尽管Treg细胞治疗的早期临床试验已在多种疾病中证实该方法的可行性与耐受性，但其疗效仍存争议。借助癌症领域原发性T细胞工程化已成功开发的智能工具与平台，该领域正转向“新一代”过继性Treg免疫治疗，通过基因修饰技术培育具有优化特性的Treg产品，在抗原特异性、功能、持久性及免疫原性等方面实现突破。本文系统综述Treg过继免疫治疗的研究现状与前沿进展，批判性评估将Tregs转化为治疗各类炎症性疾病的活体药物疗法所面临的挑战与机遇，并探讨Treg疗法向广泛临床转化的发展路径。
Promises and Pitfalls of Next-Generation Treg Adoptive Immunotherapy
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