Biederstädt Alexander, Basar Rafet, Park Jeong-Min, Uprety Nadima, Shrestha Rejeena, Reyes Silva Francia, Dede Merve, Watts John, Acharya Sunil, Xiong Donghai, Liu Bin, Daher May, Rafei Hind, Banerjee Pinaki, Li Ping, Islam Sanjida, Fan Huihui, Shanley Mayra, Jin Jingling, Kumar Bijender, Woods Vernikka, Lin Paul, Tiberti Silvia, Nunez Cortes Ana Karen, Jiang Xin Ru, Biederstädt Inci, Zhang Patrick, Li Ye, Rawal Seema, Liu Enli, Muniz-Feliciano Luis, Deyter Gary M, Shpall Elizabeth J, Fowlkes Natalie Wall, Chen Ken, Rezvani Katayoun
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Medicine III: Hematology & Oncology, School of Medicine, Technical University of Munich, Munich, Germany.
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Cancer Cell. 2025 Aug 18. doi: 10.1016/j.ccell.2025.07.021.
Adoptive cell therapy using engineered natural killer (NK) cells is a promising approach for cancer treatment, with targeted gene editing offering the potential to further enhance their therapeutic efficacy. However, the spectrum of actionable genetic targets to overcome tumor and microenvironment-mediated immunosuppression remains largely unexplored. We performed multiple genome-wide CRISPR screens in primary human NK cells and identified critical checkpoints regulating resistance to immunosuppressive pressures. Ablation of MED12, ARIH2, and CCNC significantly improved NK cell antitumor activity against multiple treatment-refractory human cancers in vitro and in vivo. CRISPR editing augmented both innate and CAR-mediated NK cell function, associated with enhanced metabolic fitness, increased secretion of proinflammatory cytokines, and expansion of cytotoxic NK cell subsets. Through high-content genome-wide CRISPR screening in NK cells, this study reveals critical regulators of NK cell function and provides a valuable resource for engineering next-generation NK cell therapies with improved efficacy against cancer.
使用工程化自然杀伤（NK）细胞的过继性细胞疗法是一种很有前景的癌症治疗方法，靶向基因编辑有可能进一步提高其治疗效果。然而，克服肿瘤和微环境介导的免疫抑制的可操作基因靶点谱在很大程度上仍未得到探索。我们在原代人NK细胞中进行了多次全基因组CRISPR筛选，并确定了调节对免疫抑制压力抗性的关键检查点。敲除MED12、ARIH2和CCNC可显著提高NK细胞在体外和体内对多种难治性人类癌症的抗肿瘤活性。CRISPR编辑增强了先天免疫和CAR介导的NK细胞功能，这与增强的代谢适应性、促炎细胞因子分泌增加以及细胞毒性NK细胞亚群的扩增有关。通过在NK细胞中进行高内涵全基因组CRISPR筛选，本研究揭示了NK细胞功能的关键调节因子，并为设计对癌症疗效更佳的下一代NK细胞疗法提供了宝贵资源。
