NK 细胞的悠久历史始于大约 50 年前，当时首次证明了循环白细胞的一个未定义亚群中具有天然细胞毒性活性，越来越多的研究人员参与其中，他们着迷于这个看似容易实现的目标： “通用抗肿瘤免疫工具”。事实上，尽管在最初的几十年中取得了令人印象深刻的进展，但事实证明这些细胞比预期复杂得多，而且矛盾的是，不断积累的发现不断推动了免疫治疗功能的完全控制。近几年的精细研究表明，NK 细胞可以通过表观遗传学来校准其功能潜力，以响应特定的环境背景，从而产生极其多样化的亚群，包括记忆样细胞、组织驻留细胞或各种分化细胞。阶段或不同的功能状态。此外，NK 细胞可以调整其活性以响应复杂的信号，从与抑制性或刺激性细胞（分别为骨髓源性抑制细胞或树突状细胞）的相互作用到与各种受体（特定于免疫细胞）的结合检查点、细胞因子、肿瘤/病毒配体或介导抗体依赖性细胞介导的细胞毒性）。根据这张图片，简单而广泛地利用 NK 细胞的想法正在发生变化，并且为新的精心设计、组合和个性化治疗策略开辟了道路，该策略也是基于使用转基因 NK 细胞和能够增强疗效的刺激。并重新调整其效应器功能以对抗癌症。© 2024 作者。经泰勒许可出版

The long story of NK cells started about 50 y ago with the first demonstration of a natural cytotoxic activity within an undefined subset of circulating leukocytes, has involved an ever-growing number of researchers, fascinated by the apparently easy-to-reach aim of getting a "universal anti-tumor immune tool". In fact, in spite of the impressive progress obtained in the first decades, these cells proved far more complex than expected and, paradoxically, the accumulating findings have continuously moved forward the attainment of a complete control of their function for immunotherapy. The refined studies of these latter years have indicated that NK cells can epigenetically calibrate their functional potential, in response to specific environmental contexts, giving rise to extraordinarily variegated subpopulations, comprehensive of memory-like cells, tissue-resident cells, or cells in various differentiation stages, or distinct functional states. In addition, NK cells can adapt their activity in response to a complex body of signals, spanning from the interaction with either suppressive or stimulating cells (myeloid-derived suppressor cells or dendritic cells, respectively) to the engagement of various receptors (specific for immune checkpoints, cytokines, tumor/viral ligands, or mediating antibody-dependent cell-mediated cytotoxicity). According to this picture, the idea of an easy and generalized exploitation of NK cells is changing, and the way is opening toward new carefully designed, combined and personalized therapeutic strategies, also based on the use of genetically modified NK cells and stimuli capable of strengthening and redirecting their effector functions against cancer.© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.