This study presents a comprehensive transcriptional reference map of healthy human blood- and tissue-derived natural killer (NK) cells, integrating single-cell RNA sequencing (scRNA-seq) data from 44,640 peripheral blood (PB) NK cells and 27,732 tissue-resident NK (TrNK) cells. The reference map was used to analyze tumor-infiltrating NK cells (TINK) from 39 datasets of 7 solid tumors and 427 patients. The analysis identified six functionally distinct NK cell states, including a dysfunctional stressed CD56bright state and a cytotoxic TME-resistant effector CD56dim state, which were enriched across various tumor types. The ratio of these two states was predictive of patient outcome in malignant melanoma and osteosarcoma. The study highlights the importance of understanding the molecular programs driving NK cell differentiation and functional diversification, and provides insights into how the tumor microenvironment (TME) can perturb NK cell function, potentially leading to immunosuppression. The resource can inform the design of new NK cell therapies and can be extended to interrogate new datasets from experimental perturbations or disease conditions.This study presents a comprehensive transcriptional reference map of healthy human blood- and tissue-derived natural killer (NK) cells, integrating single-cell RNA sequencing (scRNA-seq) data from 44,640 peripheral blood (PB) NK cells and 27,732 tissue-resident NK (TrNK) cells. The reference map was used to analyze tumor-infiltrating NK cells (TINK) from 39 datasets of 7 solid tumors and 427 patients. The analysis identified six functionally distinct NK cell states, including a dysfunctional stressed CD56bright state and a cytotoxic TME-resistant effector CD56dim state, which were enriched across various tumor types. The ratio of these two states was predictive of patient outcome in malignant melanoma and osteosarcoma. The study highlights the importance of understanding the molecular programs driving NK cell differentiation and functional diversification, and provides insights into how the tumor microenvironment (TME) can perturb NK cell function, potentially leading to immunosuppression. The resource can inform the design of new NK cell therapies and can be extended to interrogate new datasets from experimental perturbations or disease conditions.