Select subsets of immune effector cells have the greatest propensity to mediate antitumor responses. However, procuring these subsets is challenging, and cell-based immunotherapy is hampered by limited effector-cell persistence and lack of on-demand availability. To address these limitations, we generated a triple-gene-edited induced pluripotent stem cell (iPSC). The clonal iPSC line was engineered to express a high affinity, non-cleavable version of the Fc receptor CD16a and a membrane-bound interleukin (IL)-15/IL-15R fusion protein. The third edit was a knockout of the ecto-enzyme CD38, which hydrolyzes NAD⁺. Natural killer (NK) cells derived from these uniformly engineered iPSCs, termed iADAPT, displayed metabolic features and gene expression profiles mirroring those of cytomegalovirus-induced adaptive NK cells. iADAPT NK cells persisted in vivo in the absence of exogenous cytokine and elicited superior antitumor activity. Our findings suggest that unique subsets of the immune system can be modeled through iPSC technology for effective treatment of patients with advanced cancer.

选定的免疫效应细胞亚群最有可能介导抗肿瘤反应。然而，获得这些子集具有挑战性，并且基于细胞的免疫疗法受到有限的效应细胞持久性和缺乏按需可用性的阻碍。为了解决这些限制，我们生成了三重基因编辑的诱导多能干细胞 (iPSC)。克隆 iPSC 细胞系被设计为表达高亲和力、不可切割的 Fc 受体 CD16a 和膜结合白细胞介素 (IL)-15/IL-15R 融合蛋白。第三次编辑是外酶 CD38 的敲除，它水解 NAD ⁺. 来自这些统一改造的 iPSC 的自然杀伤 (NK) 细胞，称为 iADAPT，显示出与巨细胞病毒诱导的适应性 NK 细胞相似的代谢特征和基因表达谱。iADAPT NK 细胞在没有外源性细胞因子的情况下在体内持续存在并引发优异的抗肿瘤活性。我们的研究结果表明，可以通过 iPSC 技术对免疫系统的独特子集进行建模，以有效治疗晚期癌症患者。