自然杀伤细胞（NK细胞）具有针对恶性细胞的自发细胞毒性能力，并有望成为针对癌症的现成细胞疗法。该领域的一个关键挑战是改善NK细胞对实体肿瘤的归巢能力。为了更深入地了解调节NK细胞进入肿瘤的细胞机制，我们使用高维流式细胞术、质谱细胞术和单细胞RNA测序结合功能分析，创建了人类NK细胞迁移表型的全面图谱。我们发现，外周血NK细胞的趋化因子受体重排以协调的方式发生改变，在NK细胞分化过程中逐渐多样化，并与不同NK细胞亚群的迁移反应紧密相关。CXCR1/2和CX3CR1的同时结合，协同增强了NK细胞的迁移反应。对来自公开的TCGA/TARGET数据库的9471个实体癌症的分析显示，占优势的趋化因子模式因肿瘤类型而异，但没有任何肿瘤组表达成熟NK细胞上的多个趋化因子受体配体。发现趋化因子刺激可以在NK细胞中引发协同的迁移反应，结合人类肿瘤中缺乏自然存在的趋化因子-趋化因子受体对解释了NK细胞在肿瘤微环境中的系统性排斥，并为构建下一代针对恶性肿瘤的NK细胞疗法提供了依据。波兰科学与高等教育部、波兰国家科学中心、挪威癌症协会、挪威研究委员会、挪威东南部地区卫生局、瑞典癌症协会、瑞典儿童癌症基金会、瑞典研究委员会、卓越中心：精准免疫疗法联盟、Knut和Alice Wallenberg基金会和美国国家癌症研究所。版权所有 © 2023 作者授权 Elsevier B.V. 出版，版权所有。

Natural killer (NK) cells have a unique capability of spontaneous cytotoxicity against malignant cells and hold promise for off-the-shelf cell therapy against cancer. One of the key challenges in the field is to improve NK cell homing to solid tumors.To gain a deeper understanding of the cellular mechanisms regulating trafficking of NK cells into the tumor, we used high-dimensional flow cytometry, mass cytometry, and single-cell RNA-sequencing combined with functional assays, creating a comprehensive map of human NK cell migration phenotypes.We found that the chemokine receptor repertoire of peripheral blood NK cells changes in a coordinated manner becoming progressively more diversified during NK cell differentiation and correlating tightly with the migratory response of the distinct NK cell subsets. Simultaneous ligation of CXCR1/2 and CX3CR1, synergistically potentiated the migratory response of NK cells. Analysis of 9471 solid cancers from publicly available TCGA/TARGET repositories revealed dominant chemokine patterns that varied across tumor types but with no tumor group expressing ligands for more than one chemokine receptor present on mature NK cells.The finding that chemokine stimulation can elicit a synergistic migratory response in NK cells combined with the identified lack of naturally occurring pairs of chemokines-chemokine receptors in human cancers may explain the systematic exclusion of NK cells from the tumor microenvironment and provides a basis for engineering next-generation NK cell therapies against malignancies.The Polish Ministry of Science and Higher Education, the National Science Centre, Poland, The Norwegian Cancer Society, the Norwegian Research Council, the South-Eastern Norway Regional Health Authority, The Swedish Cancer Society, the Swedish Children's Cancer Foundation, The Swedish Research Council, The Center of Excellence: Precision Immunotherapy Alliance, Knut and Alice Wallenberg Foundation and National Cancer Institute.Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.