采用嵌合抗原受体（CAR）工程化T细胞的养育免疫疗法能够有效地引发对造血恶性肿瘤的抗肿瘤反应。然而，大多数患者在其效果上并不持久，因而需要进一步提高T细胞功能。细胞因子信号转导是调控T细胞存活和效应功能的关键级联之一。除了使用共同的γ链作为受体亚单位的细胞因子外，多种细胞因子直接或间接调节T细胞功能。通过基因工程调节CAR-T细胞中的细胞因子信号转导是增强其治疗效力的一种有前景的策略。这些策略包括细胞因子、细胞因子受体的异位表达以及模拟内源性细胞因子信号传导的合成分子。另外，通过转录和表观遗传修饰可以重新编程CAR-T细胞的特性，从而增强自主分泌的IL-2信号转导。另一方面，CAR-T细胞产生的细胞因子会引发全身性炎症反应，主要表现为不良事件，如细胞因子释放综合征和神经毒性。除了抑制来自活化巨噬细胞释放的直接炎性介质（如IL-6和IL- 1），通过基因修饰CAR-T细胞可以抑制与巨噬细胞刺激相关的T细胞源性细胞因子。在本综述文章中，将概述最近发展的合成生物学方法，以利用细胞因子信号转导来增强CAR-T细胞的功能。还将讨论预防或减轻CAR-T细胞相关毒性的治疗靶标分子。©2023作者。由牛津大学出版社代表日本免疫学学会发表。

Adoptive immunotherapy using chimeric antigen receptor (CAR)-engineered T cells can induce robust antitumor responses against hematologic malignancies. However, its efficacy is not durable in the majority of the patients, warranting further improvement of T cell functions. Cytokine signaling is one of the key cascades regulating T cell survival and effector functions. In addition to cytokines that use the common γ chain as a receptor subunit, multiple cytokines regulate T cell functions directly or indirectly. Modulating cytokine signaling in CAR-T cells by genetic engineering is one promising strategy to augment their therapeutic efficacy. These strategies include ectopic expression of cytokines, cytokine receptors and synthetic molecules that mimic endogenous cytokine signaling. Alternatively, autocrine IL-2 signaling can be augmented through reprogramming of CAR-T cell properties through transcriptional and epigenetic modification. On the other hand, cytokine production by CAR-T cells triggers systemic inflammatory responses, which mainly manifest as adverse events such as cytokine-release syndrome and neurotoxicity. In addition to inhibiting direct inflammatory mediators such as IL-6 and IL-1 released from activated macrophages, suppression of T cell-derived cytokines associated with the priming of macrophages can be accomplished through genetic modification of CAR-T cells. In this review, I will outline recently developed synthetic biology approaches to exploit cytokine signaling to enhance CAR-T cell functions. I will also discuss therapeutic target molecules to prevent or alleviate CAR-T cell-related toxicities.© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Society for Immunology.