A pan-cancer single-cell panorama of human natural killer cells

Natural killer (NK) cells play indispensable roles in innate immune responses against tumor progression. To depict their phenotypic and functional diversities in the tumor microenvironment, we perform integrative single-cell RNA sequencing analyses on NK cells from 716 patients with cancer, covering 24 cancer types. We observed heterogeneity in NK cell composition in a tumor-type-specific manner. Notably, we have identified a group of tumor-associated NK cells that are enriched in tumors, show impaired anti-tumor functions, and are associated with unfavorable prognosis and resistance to immunotherapy. Specific myeloid cell subpopulations, in particular LAMP3+ dendritic cells, appear to mediate the regulation of NK cell anti-tumor immunity. Our study provides insights into NK-cell-based cancer immunity and highlights potential clinical utilities of NK cell subsets as therapeutic targets. [Display omitted] •Human NK cells exhibit tumor-type-specific subgroup heterogeneity•RGS1 expression is a reliable marker of tissue-infiltrating NK cells•Transcriptomic features of tumor-associated NK cells indicate impaired cytotoxicity•LAMP3+ DCs appear to regulate NK cell functions in tumors based on spatial analyses Integrative single-cell RNA sequencing analyses on natural killer (NK) cells from over 700 patients across 24 tumor types depict shared and tumor-type-specific NK cell features and highlight the potential of specific myeloid cell subpopulations in regulating NK cell anti-tumor function.