肿瘤细胞治疗研究
英文原题：Overcoming barriers in CAR-NK immunotherapy: CRISPR-Driven advances in checkpoint editing and allogeneic design.
嵌合抗原受体（CAR）工程化自然杀伤（NK）细胞正成为癌症免疫治疗中一条令人振奋的途径，因为它们对恶性细胞具有强效细胞毒性，且相比传统T细胞疗法，移植物抗宿主病（GvHD）风险更低。
嵌合抗原受体（CAR）工程化的自然杀伤（NK）细胞因其对恶性细胞具有强效细胞毒性，且相比传统T细胞疗法具有更低的移植物抗宿主病（GvHD）风险，正成为癌症免疫治疗中一条令人振奋的途径。CRISPR/Cas9基因组编辑新技术能够实现简便、多重且精确的改变，以增强CAR-NK细胞的疗效、持久性和对肿瘤的特异性，从而显著加速了CAR-NK细胞的工程化改造。本综述聚焦于将CRISPR技术整合到CAR-NK细胞开发中。它探讨了敲除抑制性检查点基因（CISH、PD-1和TGFBR2）的用途，以及将CAR敲入安全的基因组位置和对CAR-NK细胞进行多重编辑，以提高对癌症的细胞毒性，同时抵抗肿瘤微环境（TME）的抑制。我们进一步探索了通过敲入IL-15或IL-12实现的免疫细胞因子装甲策略，以确保NK细胞的长期增殖和存活，并研究了CRISPR介导的对NKG2A和TIGIT等免疫抑制因子的敲除，以规避肿瘤用于逃避免疫破坏的免疫策略。此外，CRISPR介导的归巢受体上调增强了NK细胞的肿瘤浸润，解决了治疗实体瘤的一大障碍。值得一提的是，在生成现货型产品方面取得的进展，这是支持追求异体疗法的关键一步。尽管已取得实质性进展，但在优化CRISPR递送、脱靶效应以及增强体内持久性方面仍存在挑战。CAR-NK研究的未来方向可能会利用下一代基因组编辑工具和合成生物学，开发可调控和逻辑门控的CAR-NK细胞。总体而言，本综述阐述了将CRISPR技术与CAR-NK免疫疗法相结合，以开发针对血液系统恶性肿瘤和实体恶性肿瘤的下一代可编程且有效的治疗方法的革命性能力。
Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells are emerging as an exciting avenue in cancer immunotherapy due to their potent cytotoxicity to malignant cells and lower risk of graft-versus-host disease (GvHD) than conventional T cell therapies. The new technology of CRISPR/Cas9 genome editing has significantly expedited the engineering of CAR-NK cells by enabling easy, multiplex, and precise changes to enhance their efficacy, persistence, and specificity to tumors. This review focuses on the incorporation of CRISPR technology into CAR-NK cell development. It examines uses of knockout of inhibitory checkpoint genes (CISH, PD-1, and TGFBR2), as well as knock-in of CAR into safe genomic locations and multiplex editing of CAR-NK cells to improve cytotoxicity against cancer while resisting suppression from the tumor microenvironment (TME). We further explore immuno-cytokine armoring strategies by knock-in of IL-15 or IL-12, to ensure prolonged proliferation and survival of NK cells, and investigate CRISPR-mediated knockouts of immune inhibitors like NKG2A and TIGIT, to evade immune strategies used by the tumor to evade immune destruction. Furthermore, CRISPR-mediated upregulation of the homing receptor enhances NK cell tumor infiltration, addressing a major obstacle in treating solid tumors. It is significant to mention the progress in generating off-the-shelf products, which is a key step supporting the pursuit of allogeneic therapies. While substantial progress has been made, challenges remain related to optimizing CRISPR delivery, off-target effects, and enhancing in vivo persistence. Future directions of CAR-NK studies will likely capitalize on next-generation genome editing tools and synthetic biology for the development of tunable and logic-gated CAR-NK cells. Overall, this review illustrates the revolutionary capacity of combining CRISPR technology with CAR-NK immunotherapy to develop next-generation programmable and efficacious treatments for hematologic and solid malignancies.
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