RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
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
英文原题：Genome-wide CRISPR screens identify critical targets to enhance CAR-NK cell antitumor potency.
查看英文原题
Genome-wide CRISPR screens identify critical targets to enhance CAR-NK cell antitumor potency.
分数与星级只用于站内排序 —— 不代表疗效、安全性或个人适用性。
中文摘要
采用工程化 NK 细胞的过继细胞治疗是有前景的癌症治疗方法，靶向基因编辑可能进一步增强其疗效。然而，可用于克服肿瘤及微环境介导免疫抑制的遗传靶点谱尚未充分探索。研究者在原代人 NK 细胞中进行了多项全基因组 CRISPR 筛选，鉴定出调节免疫抑制压力抵抗能力的关键检查点。敲除 MED12、ARIH2 和 CCNC 显著增强 NK 细胞对多种治疗难治性人类癌症的体内外抗肿瘤活性。CRISPR 编辑增强了 NK 细胞的先天和 CAR 介导功能，并与代谢适应性提升、促炎细胞因子分泌增加及细胞毒性 NK 亚群扩增相关。通过在 NK 细胞中开展高内涵全基因组 CRISPR 筛选，本研究揭示了 NK 细胞功能的关键调节因子，并提供宝贵资源，可用于工程化开发疗效更佳的下一代 NK 细胞疗法。
展开英文摘要原文
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.
论文信息
- 作者
- Biederstädt A、Basar R、Park JM、Uprety N、Shrestha R、Reyes Silva F、Dede M、Watts J
- 第一作者单位
- 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.United States
- 通讯作者单位
- 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. Electronic address: krezvani@mdanderson.org.United States
- 期刊
- Cancer cell2025 Nov 10
- 原文标识
- PubMed 40845844 · DOI 10.1016/j.ccell.2025.07.021