Natural killer (NK) cells play a crucial role in host immunity by detecting cells that downregulate MHC class I presentation and upregulate stress ligands, as commonly seen in cancers. Current NK therapies using primary NK cells are prone to manufacturing issues related to expansion and storage. Alternative cell sources utilizing immortalized NK cell lines require irradiation and are dependent on systemic IL-2 administration, which has been associated with adverse effects. In contrast, NK cells differentiated from induced pluripotent stem cells (iPSC-NK cells) offer an off-the-shelf alternative that may overcome these bottlenecks. The development of a serum-free and feeder-free differentiation protocol allows for the manufacturing of clinically adaptable iPSC-NK cells that are equally as effective as primary NK cells and the NK-92 cell line for many indications. Moreover, genetic modifications targeting NK-mediated antibody-dependent cellular cytotoxicity capabilities, cytotoxicity, and checkpoint inhibitors may increase the therapeutic potential of iPSC-NK products. This review will highlight the current sources for NK therapies and their respective constraints, discuss recent developments in the manufacturing and genetic engineering of iPSC-NK cells, and provide an overview of ongoing clinical trials using NK cells.

中文翻译：

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诱导多能干细胞的基因组工程以制造自然杀伤细胞疗法。

自然杀伤 (NK) 细胞通过检测下调 MHC I 类呈递并上调应激配体（如癌症中常见的细胞）的细胞，在宿主免疫中发挥至关重要的作用。目前使用原代 NK 细胞的 NK 疗法容易出现与扩增和储存相关的制造问题。利用永生化 NK 细胞系的替代细胞来源需要照射，并且依赖于全身性 IL-2 给药，这会带来不良反应。相比之下，从诱导多能干细胞（iPSC-NK 细胞）分化而来的 NK 细胞提供了一种现成的替代方案，可以克服这些瓶颈。无血清和无饲养层分化方案的开发允许生产临床适应性的 iPSC-NK 细胞，这些细胞在许多适应症上与原代 NK 细胞和 NK-92 细胞系同样有效。此外，针对 NK 介导的抗体依赖性细胞毒性能力、细胞毒性和检查点抑制剂的基因修饰可能会增加 iPSC-NK 产品的治疗潜力。这篇综述将重点介绍 NK 疗法的当前来源及其各自的限制，讨论 iPSC-NK 细胞制造和基因工程的最新进展，并概述正在进行的使用 NK 细胞的临床试验。