Chimeric antigen receptor (CAR)-engineered T-cell (CAR-T) therapy has demonstrated impressive therapeutic efficacy against hematological malignancies, but multiple challenges have hindered its application, particularly for the eradication of solid tumors. Innate killer cells (IKCs), particularly NK cells, NKT cells, and γδ T cells, employ specific antigen-independent innate tumor recognition and cytotoxic mechanisms that simultaneously display high antitumor efficacy and prevent tumor escape caused by antigen loss or modulation. IKCs are associated with a low risk of developing GVHD, thus offering new opportunities for allogeneic “off-the-shelf” cellular therapeutic products. The unique innate features, wide tumor recognition range, and potent antitumor functions of IKCs make them potentially excellent candidates for cancer immunotherapy, particularly serving as platforms for CAR development. In this review, we first provide a brief summary of the challenges hampering CAR-T-cell therapy applications and then discuss the latest CAR-NK-cell research, covering the advantages, applications, and clinical translation of CAR- and NK-cell receptor (NKR)-engineered IKCs. Advances in synthetic biology and the development of novel genetic engineering techniques, such as gene-editing and cellular reprogramming, will enable the further optimization of IKC-based anticancer therapies.

嵌合抗原受体 (CAR) 工程化 T 细胞 (CAR-T) 疗法已证明对血液恶性肿瘤具有令人印象深刻的治疗效果，但多重挑战阻碍了其应用，特别是在根除实体瘤方面。先天性杀伤细胞 (IKC)，特别是 NK 细胞、NKT 细胞和 γδ T 细胞，采用特定的抗原非依赖性先天性肿瘤识别和细胞毒性机制，同时显示出高抗肿瘤功效并防止由抗原丢失或调节引起的肿瘤逃逸。IKCs 与发生 GVHD 的风险较低有关，因此为同种异体“现成”细胞治疗产品提供了新的机会。IKCs 独特的先天特征、广泛的肿瘤识别范围和强大的抗肿瘤功能使其成为癌症免疫治疗的潜在优秀候选者，特别是作为 CAR 开发的平台。在这篇综述中，我们首先简要总结了阻碍 CAR-T 细胞治疗应用的挑战，然后讨论了最新的 CAR-NK 细胞研究，涵盖了 CAR 和 NK 细胞受体的优势、应用和临床转化(NKR) 设计的 IKC。合成生物学的进步和基因编辑和细胞重编程等新型基因工程技术的发展，将使基于 IKC 的抗癌疗法得到进一步优化。CAR 和 NK 细胞受体 (NKR) 改造的 IKC 的临床转化。合成生物学的进步和基因编辑和细胞重编程等新型基因工程技术的发展，将使基于 IKC 的抗癌疗法得到进一步优化。CAR 和 NK 细胞受体 (NKR) 改造的 IKC 的临床转化。合成生物学的进步和基因编辑和细胞重编程等新型基因工程技术的发展，将使基于 IKC 的抗癌疗法得到进一步优化。