采用嵌合抗原受体（CAR）T细胞的细胞免疫治疗在多种血液肿瘤的治疗中引发了一次范式转变。然而，这种方法在髓系肿瘤和实体肿瘤的广泛应用受到了靶抗原表达的稀少和异质性的限制，同时缺乏真正的肿瘤特异性抗原，这些抗原可以在不与正常组织发生交叉反应的情况下被靶向。这可能导致非期望的靶向偏离肿瘤的毒性反应，从而削弱预期的抗肿瘤效果。最近合成生物学和基因工程的进展使得免疫效应细胞的重编程变得可能，以增强它们对肿瘤的选择性，从而减轻靶向偏离肿瘤的不良反应。在本综述中，我们概述了目前正在探索的改进CAR对肿瘤细胞选择性的策略，重点关注自然杀伤细胞（NK细胞），并介绍了将这些策略转化为临床应用的进展。© 2023 The Authors. Immunological Reviews published by John Wiley & Sons Ltd.

Adoptive cellular therapy using chimeric antigen receptor (CAR) T cells has led to a paradigm shift in the treatment of various hematologic malignancies. However, the broad application of this approach for myeloid malignancies and solid cancers has been limited by the paucity and heterogeneity of target antigen expression, and lack of bona fide tumor-specific antigens that can be targeted without cross-reactivity against normal tissues. This may lead to unwanted on-target off-tumor toxicities that could undermine the desired antitumor effect. Recent advances in synthetic biology and genetic engineering have enabled reprogramming of immune effector cells to enhance their selectivity toward tumors, thus mitigating on-target off-tumor adverse effects. In this review, we outline the current strategies being explored to improve CAR selectivity toward tumor cells with a focus on natural killer (NK) cells, and the progress made in translating these strategies to the clinic.© 2023 The Authors. Immunological Reviews published by John Wiley & Sons Ltd.