Natural killer (NK) cells comprise a unique population of innate lymphoid cells endowed with intrinsic abilities to identify and eliminate virally infected cells and tumour cells. Possessing multiple cytotoxicity mechanisms and the ability to modulate the immune response through cytokine production, NK cells play a pivotal role in anticancer immunity. This role was elucidated nearly two decades ago, when NK cells, used as immunotherapeutic agents, showed safety and efficacy in the treatment of patients with advanced-stage leukaemia. In recent years, following the paradigm-shifting successes of chimeric antigen receptor (CAR)-engineered adoptive T cell therapy and the advancement in technologies that can turn cells into powerful antitumour weapons, the interest in NK cells as a candidate for immunotherapy has grown exponentially. Strategies for the development of NK cell-based therapies focus on enhancing NK cell potency and persistence through co-stimulatory signalling, checkpoint inhibition and cytokine armouring, and aim to redirect NK cell specificity to the tumour through expression of CAR or the use of engager molecules. In the clinic, the first generation of NK cell therapies have delivered promising results, showing encouraging efficacy and remarkable safety, thus driving great enthusiasm for continued innovation. In this Review, we describe the various approaches to augment NK cell cytotoxicity and longevity, evaluate challenges and opportunities, and reflect on how lessons learned from the clinic will guide the design of next-generation NK cell products that will address the unique complexities of each cancer.

自然杀伤 (NK) 细胞包含一个独特的先天淋巴细胞群，这些细胞具有识别和消除病毒感染细胞和肿瘤细胞的内在能力。NK 细胞具有多种细胞毒性机制和通过细胞因子产生调节免疫反应的能力，在抗癌免疫中起着举足轻重的作用。这种作用在近二十年前就得到了阐明，当时用作免疫治疗剂的 NK 细胞在治疗晚期白血病患者时显示出安全性和有效性。近年来，随着嵌合抗原受体 (CAR) 改造的过继性 T 细胞疗法取得范式转变的成功以及可将细胞转变为强大抗肿瘤武器的技术进步，人们对 NK 细胞作为免疫疗法候选者的兴趣呈指数级增长. 基于 NK 细胞的疗法的开发策略侧重于通过共刺激信号、检查点抑制和细胞因子装甲来增强 NK 细胞的效力和持久性，并旨在通过 CAR 的表达或接合分子的使用将 NK 细胞特异性重定向到肿瘤. 在临床上，第一代NK细胞疗法取得了可喜的成果，显示出令人鼓舞的疗效和卓越的安全性，从而激发了人们继续创新的巨大热情。在这篇综述中，我们描述了增强 NK 细胞细胞毒性和寿命的各种方法，评估了挑战和机遇，并反思了从临床中吸取的经验教训将如何指导下一代 NK 细胞产品的设计，这些产品将解决每种细胞的独特复杂性癌症。