A pan-cancer single-cell atlas reveals tissue-specific NK cell states and therapeutic remodeling during immune checkpoint blockade

Tumor-infiltrating natural killer (NK) cells are transcriptionally and functionally heterogeneous, but their subtype diversity, tissue-specific regulation, and roles in immunotherapy remain incompletely understood. Here, we generated a pan-cancer single-cell transcriptomic atlas of NK cells across 11 cancer types, including peripheral blood, primary tumors, normal tissues, and non-metastatic and metastatic lymph nodes. This atlas revealed context-dependent remodeling of NK-cell cytotoxicity, inhibitory signaling, and communication with stromal and immune cells. We identified a previously uncharacterized immunosuppressive CSF1⁺ NK-cell subset that promotes M2-like macrophage polarization and is associated with poor overall survival. We further characterized dynamic remodeling of NK-cell functional states during immune checkpoint inhibitor (ICI) therapy, suggesting a potential role for NK-cell state transitions in immunotherapy response. Together, these findings define the tissue- and therapy-associated heterogeneity of NK cells across cancers and provide a resource for developing NK-cell-centered immunotherapeutic strategies.