采用养护T细胞转移（ACT）疗法，包括转移肿瘤浸润淋巴细胞（TILs）和基因修饰的T细胞，使其表达T细胞受体（TCR）或嵌合抗原受体（CAR），已经在某些患者和癌症类型中显示出临床疗效。ACT领域的发展得益于CD19-CAR疗法在各种晚期B细胞恶性肿瘤中的临床成功，包括对某些白血病患者的治愈反应。然而，复发问题仍然存在，尤其是淋巴瘤。此外，由于各种原因，对非血液性实体肿瘤的ACT疗法的疗效相对有限。事实上，在输注前的挑战，包括淋巴细胞的收集和制造过程中，ACT的失败可以归因于转移后的几个生物过程，包括：（i）肿瘤的移行、浸润、扩增和保留效率低下，（ii）慢性抗原暴露，伴随着不足的共刺激，导致T细胞枯竭，（iii）肿瘤微环境（TME）中由肿瘤细胞和免疫抑制性浸润介导的一系列障碍，（iv）肿瘤抗原异质性和抗原呈递机制的降低或失去，（v）对凋亡具有耐药性的肿瘤内在机制的表达增加，以及（vi）导致患者各种形式的毒性和其他不良事件。亲和力优化的TCR可以改善T细胞功能，创新的CAR设计以及基因修饰策略可以用于共同工程化T细胞的特异性、安全性和功能。共同工程策略不仅可以直接支持转移的T细胞，还可以阻断TME中的抑制性障碍，并利用内源性的先天和适应性免疫。本文对近年来发展起来的一些显著T细胞共同工程策略进行了综述，其中包括工具、受体和基因负载，这些策略旨在通过ACT增强肿瘤的控制。这些策略中越来越多的策略正在不断推进应用于临床。Immunological Reviews© 2023 The Authors. Immunological Reviews published by John Wiley & Sons Ltd.

Adoptive T-cell transfer (ACT) therapies, including of tumor infiltrating lymphocytes (TILs) and T cells gene-modified to express either a T cell receptor (TCR) or a chimeric antigen receptor (CAR), have demonstrated clinical efficacy for a proportion of patients and cancer-types. The field of ACT has been driven forward by the clinical success of CD19-CAR therapy against various advanced B-cell malignancies, including curative responses for some leukemia patients. However, relapse remains problematic, in particular for lymphoma. Moreover, for a variety of reasons, relative limited efficacy has been demonstrated for ACT of non-hematological solid tumors. Indeed, in addition to pre-infusion challenges including lymphocyte collection and manufacturing, ACT failure can be attributed to several biological processes post-transfer including, (i) inefficient tumor trafficking, infiltration, expansion and retention, (ii) chronic antigen exposure coupled with insufficient costimulation resulting in T-cell exhaustion, (iii) a range of barriers in the tumor microenvironment (TME) mediated by both tumor cells and suppressive immune infiltrate, (iv) tumor antigen heterogeneity and loss, or down-regulation of antigen presentation machinery, (v) gain of tumor intrinsic mechanisms of resistance such as to apoptosis, and (vi) various forms of toxicity and other adverse events in patients. Affinity-optimized TCRs can improve T-cell function and innovative CAR designs as well as gene-modification strategies can be used to coengineer specificity, safety, and function into T cells. Coengineering strategies can be designed not only to directly support the transferred T cells, but also to block suppressive barriers in the TME and harness endogenous innate and adaptive immunity. Here, we review a selection of the remarkable T-cell coengineering strategies, including of tools, receptors, and gene-cargo, that have been developed in recent years to augment tumor control by ACT, more and more of which are advancing to the clinic.Immunological Reviews© 2023 The Authors. Immunological Reviews published by John Wiley & Sons Ltd.