德克萨斯大学Katayoun Rezvani团队近日取得一项新成果。经过不懈努力，他们的最新研究探明了全基因组CRISPR筛选鉴定增强CAR-NK细胞抗肿瘤效力的关键靶点。该研究于2025年8月21日发表于国际一流学术期刊《癌细胞》杂志上。

该课题组在原代人NK细胞中进行了多个全基因组CRISPR筛选，并确定了调节免疫抑制压力抗性的关键检查点。在体外和体内实验中，消融MED12、ARIH2和CCNC可显著提高NK细胞对多种难治性人类癌症的抗肿瘤活性。CRISPR编辑增强了先天和CAR介导的NK细胞功能，与增强的代谢适应性、促炎细胞因子的分泌增加和细胞毒性NK细胞亚群的扩增有关。通过在NK细胞中进行高含量的全基因组CRISPR筛选，本研究揭示了NK细胞功能的关键调控因子，并为设计下一代NK细胞疗法提供了有价值的抵抗，提高了NK细胞的抗癌功效。

据悉，过继细胞治疗主题工程自然杀伤细胞（NK细胞）是一种很有前途的癌症治疗方法，有针对性的基因编辑提供了进一步提高其治疗效果的潜力。然而，克服肿瘤和微环境介导的免疫抑制的可操作的遗传靶点的谱仍然很大程度上未被探索。

附：英文原文

Title: Genome-wide CRISPR screens identify critical targets to enhance CAR-NK cell antitumor potency

Author: Alexander Biederstdt, Rafet Basar, Jeong-Min Park, Nadima Uprety, Rejeena Shrestha, Francia Reyes Silva, Merve Dede, John Watts, Sunil Acharya, Donghai Xiong, Bin Liu, May Daher, Hind Rafei, Pinaki Banerjee, Ping Li, Sanjida Islam, Huihui Fan, Mayra Shanley, Jingling Jin, Bijender Kumar, Vernikka Woods, Paul Lin, Silvia Tiberti, Ana Karen Nunez Cortes, Xin Ru Jiang, Inci Biederstdt, Patrick Zhang, Ye Li, Seema Rawal, Enli Liu, Luis Muniz-Feliciano, Gary M. Deyter, Elizabeth J. Shpall, Natalie Wall Fowlkes, Ken Chen, Katayoun Rezvani

Issue&Volume: 2025-08-21

Abstract: 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.

DOI: 10.1016/j.ccell.2025.07.021

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00327-7