Natural killer (NK) cells, initially identified for their rapid virus-infected and leukemia cell killing and tumor destruction, are pivotal in immunity. They exhibit multifaceted roles in cancer, viral infections, autoimmunity, pregnancy, wound healing, and more. Derived from a common lymphoid progenitor, they lack CD3, B-cell, or T-cell receptors but wield high cytotoxicity via perforin and granzymes. NK cells orchestrate immune responses, secreting inflammatory IFNγ or immunosuppressive TGFβ and IL-10. CD56^dim and CD56^bright NK cells execute cytotoxicity, while CD56^bright cells also regulate immunity. However, beyond the CD56 dichotomy, detailed phenotypic diversity reveals many functional subsets that may not be optimal for cancer immunotherapy. In this review, we provide comprehensive and detailed snapshots of NK cells’ functions and states of activation and inhibitions in cancer, autoimmunity, angiogenesis, wound healing, pregnancy and fertility, aging, and senescence mediated by complex signaling and ligand-receptor interactions, including the impact of the environment. As the use of engineered NK cells for cancer immunotherapy accelerates, often in the footsteps of T-cell-derived engineering, we examine the interactions of NK cells with other immune effectors and relevant signaling and the limitations in the tumor microenvironment, intending to understand how to enhance their cytolytic activities specifically for cancer immunotherapy.

自然杀伤 （NK） 细胞最初因其快速的病毒感染和白血病细胞杀伤和肿瘤破坏而被确定，在免疫中起着关键作用。它们在癌症、病毒感染、自身免疫、怀孕、伤口愈合等方面发挥着多方面的作用。它们来源于共同的淋巴祖细胞，缺乏 CD3、B 细胞或 T 细胞受体，但通过穿孔素和颗粒酶具有很高的细胞毒性。NK 细胞协调免疫反应，分泌炎性 IFNγ 或免疫抑制性 TGFβ 和 IL-10。CD56^暗淡和 CD56^亮 NK 细胞执行细胞毒性，而 CD56^亮细胞也调节免疫力。然而，除了 CD56 二分法之外，详细的表型多样性揭示了许多可能不适合癌症免疫治疗的功能亚群。在这篇综述中，我们提供了 NK 细胞在癌症、自身免疫、血管生成、伤口愈合、怀孕和生育、衰老和衰老中的功能以及激活和抑制状态的全面而详细的快照，这些状态由复杂的信号传导和配体-受体相互作用介导，包括环境的影响。随着工程化 NK 细胞在癌症免疫治疗中的加速使用，通常追随 T 细胞衍生工程的脚步，我们研究了 NK 细胞与其他免疫效应子和相关信号的相互作用以及肿瘤微环境中的局限性，旨在了解如何增强它们的溶细胞活性专门用于癌症免疫治疗。