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

Tang, Fei; Li, Jinhu; Qi, Lu; Liu, Dongfang; Bo, Yufei; Qin, Shishang; Miao, Yuhui; Yu, Kezhuo; Hou, Wenhong; Li, Jianan; Peng, Jirun; Tian, Zhigang; Zhu, Linnan; Peng, Hui; Wang, Dongfang; Zhang, Zemin

doi:10.1016/j.cell.2023.07.034

Cited by 459Immune Cell Function and InteractionCancer Immunotherapy and BiomarkersImmune cells in cancer

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

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Tang, Fei, Li, Jinhu, Qi, Lu, Liu, Dongfang, Bo, Yufei, Qin, Shishang, Miao, Yuhui, Yu, Kezhuo +8 more·2023·Cell

DOI 10.1016/j.cell.2023.07.034

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Abstract

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.

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Metascape provides a biologist-oriented resource for the analysis of systems-level datasets
Zhou, Y., Zhou, B., Pache, L., Chang, M., Khodabakhshi, A. H., Tanaseichuk, O., Benner, C., & Chanda, S. K. (2019) · Nature Communications · doi:10.1038/s41467-019-09234-6 · Cited by 14,611 · see citing works
SCANPY: large-scale single-cell gene expression data analysis
Wolf, F. A., Angerer, P., & Theis, F. J. (2018) · Genome Biology · doi:10.1186/s13059-017-1382-0 · Cited by 8,881 · see citing works
Scenic: single-cell regulatory network inference and clustering.
Aibar, S., González-Blas, C. B., Moerman, T., Huynh-Thu, V. A., Imrichova, H., Hulselmans, G., Rambow, F., Marine, J.-C., Geurts, P., Aerts, J., et al. (2017) · Nature Methods · doi:10.1038/nmeth.4463 · Cited by 6,520 · cited 2× · see citing works
“We then identified activated regulons for both tumor-infiltrating CD56brightCD16lo and CD56dim CD16hi NK cell subsets using SCENIC.49 Importantly, the tumor-enriched c6-DNAJB1 subset exhibitedmuch higher expression of transcription factors such as KLF6 and EGR3, which are associated with the inhibition of cytotoxicity…”
Background
A guide to cancer immunotherapy: from T cell basic science to clinical practice
Waldman, A. D., Fritz, J. M., & Lenardo, M. J. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-020-0306-5 · Cited by 4,154 · see citing works
RNA velocity of single cells
La Manno, G., Soldatov, R., Zeisel, A., Braun, E., Hochgerner, H., Petukhov, V., Lidschreiber, K., Kastriti, M. E., Lönnerberg, P., Furlan, A., et al. (2018) · Nature · doi:10.1038/s41586-018-0414-6 · Cited by 4,118 · see citing works
The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity
Stanietsky, N., Simic, H., Arapovic, J., Toporik, A., Levy, O., Novik, A., Levine, Z., Beiman, M., Dassa, L., Achdout, H., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0903474106 · Cited by 3,524 · see citing works
CellPhoneDB: inferring cell–cell communication from combined expression of multi-subunit ligand–receptor complexes
Efremova, M., Vento-Tormo, M., Teichmann, S. A., & Vento-Tormo, R. (2020) · Nature Protocols · doi:10.1038/s41596-020-0292-x · Cited by 3,449 · see citing works
Generalizing RNA velocity to transient cell states through dynamical modeling
Bergen, V., Lange, M., Peidli, S., Wolf, F. A., & Theis, F. J. (2020) · Nature Biotechnology · doi:10.1038/s41587-020-0591-3 · Cited by 2,951 · see citing works
Scrublet: computational identification of cell doublets in single-cell transcriptomic data
Wolock, S. L., Lopez, R., & Klein, A. M. (2019) · Cell Systems · doi:10.1016/j.cels.2018.11.005 · Cited by 2,758 · see citing works
Scrublet: computational identification of cell doublets in single-cell transcriptomic data
Wolock, S. L., Lopez, R., & Klein, A. M. (2018) · doi:10.1101/357368 · Cited by 2,758 · see citing works
Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab
Riaz, N., Havel, J. J., Makarov, V., Desrichard, A., Urba, W. J., Sims, J. S., Hodi, F. S., Martín-Algarra, S., Mandal, R., Sharfman, W. H., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.028 · Cited by 2,401 · see citing works
Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial
Balar, A. V., Galsky, M. D., Rosenberg, J. E., Powles, T., Petrylak, D. P., Bellmunt, J., Loriot, Y., Necchi, A., Hoffman-Censits, J., Perez-Gracia, J. L., et al. (2017) · The Lancet · doi:10.1016/s0140-6736(16)32455-2 · Cited by 2,199 · see citing works
Innate Lymphoid Cells: 10 Years On
Vivier, É., Artis, D., Colonna, M., Diefenbach, A., Santo, J. P. D., Eberl, G., Koyasu, S., Locksley, R. M., McKenzie, A. N. J., Mebius, R. E., et al. (2018) · Cell · doi:10.1016/j.cell.2018.07.017 · Cited by 2,136 · see citing works
CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer
McLane, L. M., Abdel-Hakeem, M. S., & Wherry, E. J. (2019) · Annual Review of Immunology · doi:10.1146/annurev-immunol-041015-055318 · Cited by 1,973 · see citing works
NK Cells Stimulate Recruitment of cDC1 into the Tumor Microenvironment Promoting Cancer Immune Control
Böttcher, J. P., Bonavita, E., Chakravarty, P., Blees, H., Cabeza-Cabrerizo, M., Sammicheli, S., Rogers, N. C., Sahai, E., Zelenay, S., & Reis e Sousa, C. (2018) · Cell · doi:10.1016/j.cell.2018.01.004 · Cited by 1,857 · cited 2× · see citing works
“In particular, the CD56dim CD16hi subset c4-NFKBIA exhibited a relatively high inflammatory score among all NK cell subsets, predominantly expressing CCL3, CCL4, and CCL4L2, indicating their ability to recruit other immune cells such as T cells.36 Recent studies have associated the recruitment of type 1 conventional d…”
Background
Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing
Guo, X., Zhang, Y., Zheng, L., Zheng, C., Song, J., Zhang, Q., Kang, B., Liu, Z., Jin, L., Xing, R., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0045-3 · Cited by 1,651 · see citing works
Landscape and Dynamics of Single Immune Cells in Hepatocellular Carcinoma
Zhang, Q., He, Y., Luo, N., Patel, S. J., Han, Y., Gao, R., Modak, M., Carotta, S., Haslinger, C., Kind, D., et al. (2019) · Cell · doi:10.1016/j.cell.2019.10.003 · Cited by 1,624 · see citing works
Self-citation
A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells
Cheng, S., Li, Z., Gao, R., Xing, B., Gao, Y., Yang, Y., Qin, S., Zhang, L., Ouyang, H., Du, P., et al. (2021) · Cell · doi:10.1016/j.cell.2021.01.010 · Cited by 1,601 · see citing works
Self-citation
Human natural killer cells: a unique innate immunoregulatory role for the CD56bright subset
Cooper, M. A., Fehniger, T. A., Turner, S. C., Chen, K. S.-M., Ghaheri, B. A., Ghayur, T., Carson, W. E., & Caligiuri, M. A. (2001) · Blood · doi:10.1182/blood.v97.10.3146 · Cited by 1,448 · cited 1× · see citing works
“Cell 186, 1–17, Sept This is an open access article und killing of target cells by secreting perforin and granzymes,(11) whereas the CD56CD16 NK cell population exhibits immunoregulatory and cytokine-producing capacity.(12) Recently, single-cell RNA sequencing (scRNA-seq) technologies have facilitated the characteriza…”
Background
Pan-cancer single-cell landscape of tumor-infiltrating T cells
Zheng, L., Qin, S., Si, W., Wang, A., Xing, B., Gao, R., Ren, X., Wang, L., Wu, X., Zhang, J., et al. (2021) · Science · doi:10.1126/science.abe6474 · Cited by 1,402 · see citing works
Diffusion pseudotime robustly reconstructs lineage branching
Haghverdi, L., Büttner, M., Wolf, F. A., Buettner, F., & Theis, F. J. (2016) · Nature Methods · doi:10.1038/nmeth.3971 · Cited by 1,385 · see citing works
Exploring the NK cell platform for cancer immunotherapy
Myers, J. A., & Miller, J. S. (2020) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-020-0426-7 · Cited by 1,293 · cited 4× · see citing works
“of NK cells and utilized for NK cell infusion and in vitro propagation.(4,68) By contrast, TIGIT contributes to suppressing NK cellmediated immune responses as an inhibitory receptor.”
BackgroundInfluential
NK cells for cancer immunotherapy
Shimasaki, N., Jain, A., & Campana, D. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0052-1 · Cited by 1,233 · see citing works
Natural Killer Cells: Development, Maturation, and Clinical Utilization
Abel, A. M., Yang, C., Thakar, M. S., & Malarkannan, S. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01869 · Cited by 1,150 · see citing works
The relationship of CD16 (Leu-11) and Leu-19 (NKH-1) antigen expression on human peripheral blood NK cells and cytotoxic T lymphocytes.
Lanier, L. L., Le, A. M., Civin, C., Loken, M. R., & Phillips, J. H. (1986) · The Journal of Immunology · doi:10.4049/jimmunol.136.12.4480 · Cited by 1,130 · cited 1× · see citing works
“In humans, NK cells can be subdivided into two major groups, CD56CD16 and CD56CD16, based on the expression levels of CD56 (NCAM1) and CD16 (FCGR3A).(9,10) The CD56CD16 NK cell population predominantly mediates the”
Background
Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity
Zhang, Q., Bi, J., Zheng, X., Chen, Y., Wang, H., Wu, W., Wang, Z., Wu, Q., Peng, H. C., Wei, H., et al. (2018) · Nature Immunology · doi:10.1038/s41590-018-0132-0 · Cited by 1,122 · cited 2× · see citing works
“By contrast, TIGIT contributes to suppressing NK cellmediated immune responses as an inhibitory receptor.(28,69,70) Furthermore, in TCGA datasets, the abundance of LAMP3 DCs was correlated with CD56CD16 NK cells (Figures 6I, S6I, and S6J).”
Background
Dysfunctional CD8 T cells form a proliferative, dynamically regulated compartment within human melanoma
Li, H., van der Leun, A. M., Yofe, I., Lubling, Y., Gelbard-Solodkin, D., van Akkooi, A. C. J., van den Braber, M., Rozeman, E. A., Haanen, J. B. A. G., Blank, C. U., et al. (2019) · Cell · doi:10.1016/j.cell.2018.11.043 · Cited by 1,101 · see citing works
Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation
Dhatchinamoorthy, K., Colbert, J. D., & Rock, K. L. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.636568 · Cited by 1,077 · cited 1× · see citing works
“Compared with CD8 T cells, NK cells serve as alternative sources of cytotoxic activities and combat tumor cells with low mutation load and aberrant expression of major histocompatibility complex (MHC) class I.(22,23) Although the dysfunctional state of CD8 T cells is well-characterized with reduced cytotoxicity”
Background
Human iPSC-Derived Natural Killer Cells Engineered with Chimeric Antigen Receptors Enhance Anti-tumor Activity
Li, Y., Hermanson, D., Moriarity, B. S., & Kaufman, D. S. (2018) · Cell stem cell · doi:10.1016/j.stem.2018.06.002 · Cited by 986 · cited 1× · see citing works
“Of particular note is the remarkable clinical success achieved by chimeric antigen receptor (CAR)NK cell therapies in lymphoma, myeloma, and leukemia.(5,6) However, NK-cell-based therapies are hindered in solid tumors partly due to the incomplete understanding of tumor-infiltrating NK cells, especially their infiltrat…”
Background
A conserved dendritic-cell regulatory program limits antitumour immunity
Maier, B. B., Leader, A. M., Chen, S. T., Tung, N., Chang, C., Bérichel, J. L., Chudnovskiy, A., Maskey, S., Walker, L. A., Finnigan, J. P., et al. (2020) · Nature · doi:10.1038/s41586-020-2134-y · Cited by 950 · see citing works
BBKNN: fast batch alignment of single cell transcriptomes
Polański, K., Young, M. D., Miao, Z., Meyer, K. B., Teichmann, S. A., & Park, J.-E. (2020) · Bioinformatics · doi:10.1093/bioinformatics/btz625 · Cited by 932 · see citing works
NR4A transcription factors limit CAR T cell function in solid tumours
Chen, J., López-Moyado, I. F., Seo, H., Lio, C.-W. J., Hempleman, L. J., Sekiya, T., Yoshimura, A., Scott-Browne, J. P., & Rao, A. (2019) · Nature · doi:10.1038/s41586-019-0985-x · Cited by 874 · see citing works
Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell–dendritic cell interaction
Castellino, F., Huang, A. Y.-C., Altan-Bonnet, G. Y., Stoll, S., Scheinecker, C., & Germain, R. N. (2006) · Nature · doi:10.1038/nature04651 · Cited by 847 · see citing works
Cytomegalovirus Infection Drives Adaptive Epigenetic Diversification of NK Cells with Altered Signaling and Effector Function
Schlums, H., Cichocki, F. M., Tesi, B., Theorell, J., Béziat, V., Holmes, T. D., Han, H., Chiang, S. C. C., Foley, B. A., Mattsson, K., et al. (2015) · Immunity · doi:10.1016/j.immuni.2015.02.008 · Cited by 791 · cited 1× · see citing works
“CD56CD16 c8-KLRC2 NK cells with high expression of KLRC2 (NKG2C) were regarded adaptive NK cells.(32,33) Our atlas additionally uncovered several underappreciated NK cell subsets with unique transcriptional phenotypes.”
Background
Single-cell analyses reveal key immune cell subsets associated with response to PD-L1 blockade in triple-negative breast cancer
Zhang, Y., Chen, H., Mo, H., Hu, X., Gao, R., Zhao, Y., Liu, B., Niu, L., Sun, X., Yu, X., et al. (2021) · Cancer Cell · doi:10.1016/j.ccell.2021.09.010 · Cited by 783 · see citing works
Self-citation
The Broad Spectrum of Human Natural Killer Cell Diversity
Freud, A. G., Mundy-Bosse, B. L., Yu, J., & Caligiuri, M. A. (2017) · Immunity · doi:10.1016/j.immuni.2017.10.008 · Cited by 695 · see citing works
Comparative studies of human FcRIII-positive and negative natural killer cells.
Nagler, A., Lanier, L. L., Cwirla, S. E., & Phillips, J. H. (1989) · The Journal of Immunology · doi:10.4049/jimmunol.143.10.3183 · Cited by 694 · cited 1× · see citing works
“In humans, NK cells can be subdivided into two major groups, CD56CD16 and CD56CD16, based on the expression levels of CD56 (NCAM1) and CD16 (FCGR3A).(9,10) The CD56CD16 NK cell population predominantly mediates the”
Background
Mechanisms of natural killer cell-mediated cellular cytotoxicity
Prager, I., & Watzl, C. (2019) · Journal of Leukocyte Biology · doi:10.1002/jlb.mr0718-269r · Cited by 636 · see citing works
CD8+CD103+ Tumor–Infiltrating Lymphocytes Are Tumor-Specific Tissue-Resident Memory T Cells and a Prognostic Factor for Survival in Lung Cancer Patients
Djenidi, F., Adam, J., Goubar, A., Durgeau, A., Meurice, G., de Montpréville, V., Validire, P., Besse, B., & Mami-Chouaib, F. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1402711 · Cited by 622 · see citing works
The cancer–natural killer cell immunity cycle
Huntington, N. D., Cursons, J., & Rautela, J. (2020) · Nature reviews. Cancer · doi:10.1038/s41568-020-0272-z · Cited by 570 · see citing works
Liver-resident NK cells confer adaptive immunity in skin-contact inflammation
Peng, H. C., Jiang, X., Chen, Y., Sojka, D. K., Wei, H., Gao, X., Sun, R., Yokoyama, W. M., & Tian, Z. (2013) · Journal of Clinical Investigation · doi:10.1172/jci66381 · Cited by 546 · see citing works
Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells
Sojka, D. K., Plougastel-Douglas, B., Yang, L., Pak-Wittel, M. A., Artyomov, M. N., Ivanova, Y., Zhong, C., Chase, J. M., Rothman, P. B., Yu, J. L., et al. (2014) · eLife · doi:10.7554/elife.01659 · Cited by 545 · see citing works
DNA methylation loss promotes immune evasion of tumours with high mutation and copy number load
Jung, H., Kim, H. S., Kim, J. Y., Sun, J., Ahn, J. S., Ahn, M., Park, K., Esteller, M., Lee, S., & Choi, J. K. (2019) · Nature Communications · doi:10.1038/s41467-019-12159-9 · Cited by 537 · see citing works
Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction
Liu, X., Wang, Y., Lu, H., Li, J., Yan, X., Xiao, M., Hao, J., Alekseev, A., Khong, H., Chen, T., et al. (2019) · Nature · doi:10.1038/s41586-019-0979-8 · Cited by 533 · see citing works
Self-citation
Human natural killer cell development
Freud, A. G., & Caligiuri, M. A. (2006) · Immunological Reviews · doi:10.1111/j.1600-065x.2006.00451.x · Cited by 500 · cited 1× · see citing works
“Natural killer (NK) cells, as one important component in the tumor microenvironment (TME), are involved in multiple processes of tumor control, such as direct cell killing and secretion of proinflammatory cytokines.(2,3) A plethora of strategies, characterized with promising properties including their safety and effic…”
Background
The heterogeneity of human CD127+ innate lymphoid cells revealed by single-cell RNA sequencing
Björklund, Å. K., Forkel, M., Picelli, S., Kónya, V., Theorell, J., Friberg, D., Sandberg, R., & Mjösberg, J. (2016) · Nature Immunology · doi:10.1038/ni.3368 · Cited by 491 · see citing works
High-Dimensional Single-Cell Analysis Identifies Organ-Specific Signatures and Conserved NK Cell Subsets in Humans and Mice
Crinier, A., Milpied, P., Escalière, B., Piperoglou, C., Galluso, J., Balsamo, A., Spinelli, L., Cervera-Marzal, I., Ebbo, M., Girard-Madoux, M., et al. (2018) · Immunity · doi:10.1016/j.immuni.2018.09.009 · Cited by 470 · cited 1× · see citing works
“CD56CD16 NK cells displayed intermediate features between CD56CD16 and CD56CD16 NK cells (Figure S2E), potentially representing developmental intermediates in analogy to mouse CD27CD11b NK cells, which have also been thought to be a transient maturation stage in mice yet barely detectable by scRNA-seq.(17) We next exa…”
Background
Inhibition of G-protein-mediated MAP kinase activation by a new mammalian gene family
Druey, K. M., Blumer, K., Kang, V. H., & Kehrl, J. H. (1996) · Nature · doi:10.1038/379742a0 · Cited by 468 · see citing works
Developmental pathways that generate natural-killer-cell diversity in mice and humans
Huntington, N. D., Vosshenrich, C. A. J., & Santo, J. P. D. (2007) · Nature reviews. Immunology · doi:10.1038/nri2154 · Cited by 461 · cited 1× · see citing works
“Natural killer (NK) cells, as one important component in the tumor microenvironment (TME), are involved in multiple processes of tumor control, such as direct cell killing and secretion of proinflammatory cytokines.(2,3) A plethora of strategies, characterized with promising properties including their safety and effic…”
Background
Emerging insights into natural killer cells in human peripheral tissues
Björkström, N. K., Ljunggren, H., & Michaëlsson, J. (2016) · Nature reviews. Immunology · doi:10.1038/nri.2016.34 · Cited by 451 · see citing works
Egr-2 and Egr-3 are negative regulators of T cell activation
Safford, M., Collins, S. L., Lutz, M. A., Allen, A. N., Huang, C.-T., Kowalski, J., Blackford, A. L., Horton, M. R., Drake, C. G., Schwartz, R. H., et al. (2005) · Nature Immunology · doi:10.1038/ni1193 · Cited by 446 · see citing works
Co-association of CD3ζ with a receptor (CD16) for IgG Fc on human natural killer cells
Lanier, L. L., Yu, G., & Phillips, J. H. (1989) · Nature · doi:10.1038/342803a0 · Cited by 443 · see citing works
Tissue Determinants of Human NK Cell Development, Function, and Residence
Dogra, P., Rancan, C., Ma, W., Tóth, M., Senda, T., Carpenter, D. J., Kubota, M., Matsumoto, R., Thapa, P., Szabo, P. A., et al. (2020) · Cell · doi:10.1016/j.cell.2020.01.022 · Cited by 441 · cited 1× · see citing works
“Additionally, preferential expression of these markers in NK cell populations of particular tissues has been reported.(16) These motivated us to discover robust NK cell residency markers from the pan-cancer perspective in an unbiased manner.”
Background
Influence of the Tumor Microenvironment on NK Cell Function in Solid Tumors
Melaiu, O., Lucarini, V., Cifaldi, L., & Fruci, D. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2019.03038 · Cited by 418 · cited 7× · see citing works
“However, NK-cell-based therapies are hindered in solid tumors partly due to the incomplete understanding of tumor-infiltrating NK cells, especially their infiltration to tumor, phenotypic heterogeneities, and dysregulation within the TME.(7,8) In humans, NK cells can be subdivided into two major groups, CD56CD16 and C…”
BackgroundInfluential
Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma
Sangro, B., Melero, I., Wadhawan, S., Finn, R. S., Abou-Alfa, G. K., Cheng, A.-L., Yau, T., Furuse, J., Park, J.-W., Boyd, Z., et al. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.07.026 · Cited by 407 · see citing works
Tissue-resident memory and circulating T cells are early responders to pre-surgical cancer immunotherapy
Luoma, A., Suo, S., Wang, Y., Gunasti, L., Porter, C. B. M., Nabilsi, N. H., Tadros, J., Ferretti, A. P., Liao, S., Gurer, C., et al. (2022) · Cell · doi:10.1016/j.cell.2022.06.018 · Cited by 391 · see citing works
IL-15 is an essential mediator of peripheral NK-cell homeostasis
Ranson, T., Vosshenrich, C. A. J., Corcuff, E., Richard, O., Müller, W., & Santo, J. P. D. (2003) · Blood · doi:10.1182/blood-2002-11-3392 · Cited by 343 · cited 1× · see citing works
“of NK cells and utilized for NK cell infusion and in vitro propagation.(4,68) By contrast, TIGIT contributes to suppressing NK cellmediated immune responses as an inhibitory receptor.”
Background
"Tolerosomes" are produced by intestinal epithelial cells
Karlsson, M., Lundin, S. B., Dahlgren, U. I., Kahu, H., Pettersson, I., & Telemo, E. (2001) · European Journal of Immunology · doi:10.1002/1521-4141(2001010)31:10 · Cited by 303 · see citing works
Heterogeneity of human bone marrow and blood natural killer cells defined by single-cell transcriptome
Yang, C., Siebert, J., Burns, R., Gerbec, Z. J., Bonacci, B. B., Rymaszewski, A. L., Rau, M. J., Riese, M. J., Rao, S., Carlson, K.-S., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11947-7 · Cited by 298 · see citing works
High NKG2A expression contributes to NK cell exhaustion and predicts a poor prognosis of patients with liver cancer
Sun, C., Xu, J., Huang, Q., Huang, M., Wen, H., Zhang, C., Wang, J., Song, J., Zheng, M., Sun, H., et al. (2016) · OncoImmunology · doi:10.1080/2162402x.2016.1264562 · Cited by 289 · see citing works
Functional impairment in circulating and intrahepatic NK cells and relative mechanism in hepatocellular carcinoma patients
Cai, L., Zhang, Z., Zhou, L., Wang, H., Fu, J., Zhang, S., Shi, M., Zhang, H., Yang, Y., Wu, H., et al. (2008) · Clinical Immunology · doi:10.1016/j.clim.2008.08.012 · Cited by 288 · see citing works
Deep learning–based cell composition analysis from tissue expression profiles
Menden, K., Marouf, M., Oller, S., Dalmia, A., Magruder, D. S., Kloiber, K., Heutink, P., & Bonn, S. (2020) · Science Advances · doi:10.1126/sciadv.aba2619 · Cited by 258 · see citing works
Targeting natural killer cells in solid tumors
Habif, G., Crinier, A., André, P., Vivier, É., & Narni-Mancinelli, É. (2019) · Cellular and Molecular Immunology · doi:10.1038/s41423-019-0224-2 · Cited by 242 · cited 7× · see citing works
“However, NK-cell-based therapies are hindered in solid tumors partly due to the incomplete understanding of tumor-infiltrating NK cells, especially their infiltration to tumor, phenotypic heterogeneities, and dysregulation within the TME.(7,8) In humans, NK cells can be subdivided into two major groups, CD56CD16 and C…”
BackgroundInfluential
An entropy-based metric for assessing the purity of single cell populations
Liu, B., Li, C., Li, Z., Wang, D., Ren, X., & Zhang, Z. (2020) · Nature Communications · doi:10.1038/s41467-020-16904-3 · Cited by 213 · see citing works
Diversity of peripheral blood human NK cells identified by single-cell RNA sequencing
Smith, S. L., Kennedy, P. R., Stacey, K., Worboys, J. D., Yarwood, A., Seo, S., Hegewisch-Solloa, E., Mistretta, B., Chatterjee, S. S., Gunaratne, P. H., et al. (2020) · Blood Advances · doi:10.1182/bloodadvances.2019000699 · Cited by 205 · see citing works
Characterizing the Dysfunctional NK Cell: Assessing the Clinical Relevance of Exhaustion, Anergy, and Senescence
Judge, S. J., Murphy, W. J., & Canter, R. J. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.00049 · Cited by 203 · cited 1× · see citing works
“Analogous to the exhaustion of T cells,(24,74) the dysfunction of NK cells suggests the impairment of natural cytotoxicity.(75,76) Notably, although TaNK cells are not always the dominant component of tumor-infiltrating NK cells in all cancers, the enrichment of TaNK cells in tumors is robust in various cancers includ…”
Background
NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma
Sun, C., Sun, H., Zhang, C., & Tian, Z. (2014) · Cellular and Molecular Immunology · doi:10.1038/cmi.2014.91 · Cited by 201 · see citing works
Annexin A1 drives macrophage skewing to accelerate muscle regeneration through AMPK activation
McArthur, S., Juban, G., Gobbetti, T., Desgeorges, T., Théret, M., Gondin, J., Toller-Kawahisa, J. E., Reutelingsperger, C. P. M., Chazaud, B., Perretti, M., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci124635 · Cited by 199 · see citing works
CAR-NK cells for cancer immunotherapy: from bench to bedside
Zhang, L., Yuan, M., Feng, X., & Han, Z. (2022) · Biomarker Research · doi:10.1186/s40364-022-00364-6 · Cited by 195 · cited 1× · see citing works
“Of particular note is the remarkable clinical success achieved by chimeric antigen receptor (CAR)NK cell therapies in lymphoma, myeloma, and leukemia.(5,6) However, NK-cell-based therapies are hindered in solid tumors partly due to the incomplete understanding of tumor-infiltrating NK cells, especially their infiltrat…”
Background
The Transcription Factors Egr2 and Egr3 Are Essential for the Control of Inflammation and Antigen-Induced Proliferation of B and T Cells
Li, S., Miao, T., Sebastian, M., Bhullar, P., Ghaffari, E., Liu, M., Symonds, A. L. J., & Wang, P. (2012) · Immunity · doi:10.1016/j.immuni.2012.08.001 · Cited by 192 · see citing works
Role of Krüppel-like factors in leukocyte development, function, and disease
Cao, Z., Sun, X., Icli, B., Wara, A. K., & Feinberg, M. W. (2010) · Blood · doi:10.1182/blood-2010-05-285353 · Cited by 186 · see citing works
Innate lymphoid cells and cancer
Jacquelot, N., Seillet, C., Vivier, É., & Belz, G. T. (2022) · Nature Immunology · doi:10.1038/s41590-022-01127-z · Cited by 186 · see citing works
Correlation between NK function and response to trastuzumab in metastatic breast cancer patients
Beano, A., Signorino, E., Evangelista, A., Brusa, D., Mistrangelo, M., Polimeni, M. A., Spadi, R., Donadio, M., Ciuffreda, L., & Matera, L. (2008) · Journal of Translational Medicine · doi:10.1186/1479-5876-6-25 · Cited by 155 · see citing works
Discovery of specialized NK cell populations infiltrating human melanoma metastases
de Andrade, L. F., Lu, Y., Luoma, A., Ito, Y., Pan, D., Pyrdol, J. W., Yoon, C. H., Yuan, G., & Wucherpfennig, K. W. (2019) · JCI Insight · doi:10.1172/jci.insight.133103 · Cited by 151 · cited 1× · see citing works
“For example, we have identified a CD160HSPA1A liver-resident NK cell subset specifically enriched in hepatocellular carcinoma (HCC),(14) and others have reported specialized NK cell populations infiltrated in melanoma with regional variation.(15) In parallel, the distribution and function of human NK cell populations…”
NK Cell Dysfunction and Checkpoint Immunotherapy
Bi, J., & Tian, Z. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01999 · Cited by 150 · see citing works
Transcriptomic profiles of neoantigen-reactive T cells in human gastrointestinal cancers
Zheng, C., Fass, J. N., Shih, Y.-P., Gunderson, A. J., Silva, N. S., Huang, H., Bernard, B. M., Rajamanickam, V., Slagel, J., Bifulco, C. B., et al. (2022) · Cancer Cell · doi:10.1016/j.ccell.2022.03.005 · Cited by 143 · see citing works
Minimal PD-1 expression in mouse and human NK cells under diverse conditions
Judge, S. J., Dunai, C., Aguilar, E. G., Vick, S. C., Sturgill, I. R., Khuat, L. T., Stoffel, K. M., Dyke, J. V., Longo, D. L., Darrow, M. A., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci133353 · Cited by 142 · cited 1× · see citing works
“In addition, although the inhibitory roles of TIGIT and TIM3 have been established in tumor-infiltrating NK cells,(27,28) it is still controversial whether other immune checkpoints, such as PD-1 and CTLA4, play the same role or are even expressed in those cells.(28,29) Furthermore, NK cells are sensitive to immunosupp…”
Background
Natural Killer Cells Suppress T Cell-Associated Tumor Immune Evasion
Freeman, A. J., Vervoort, S. J., Ramsbottom, K. M., Kelly, M. J., Michie, J., Pijpers, L., Johnstone, R. W., Kearney, C. J., & Oliaro, J. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.08.017 · Cited by 140 · see citing works
Adaptive NK Cells Resist Regulatory T-cell Suppression Driven by IL37
Sarhan, D., Hippen, K. L., Lemire, A. M., Hying, S., Luo, X., Lenvik, T. R., Curtsinger, J., Davis, Z., Zhang, B., Cooley, S., et al. (2018) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-17-0498 · Cited by 120 · cited 1× · see citing works
“External factors from other cell populations in the TME including myeloid-derived suppressor cells, Tregs, and tumor-associated macrophages can also suppress the anti-tumor function of NK cells.(4,77) Our analyses and experimental evidence support myeloid cells as core mediators of NK cells.”
Background
Targeting regulator of G protein signaling 1 in tumor-specific T cells enhances their trafficking to breast cancer
Huang, D., Chen, X., Zeng, X., Lao, L., Li, J., Xing, Y., Lu, Y., Ouyang, Q., Chen, J., Yang, L., et al. (2021) · Nature Immunology · doi:10.1038/s41590-021-00939-9 · Cited by 114 · see citing works
Neutrophil Microvesicles from Healthy Control and Rheumatoid Arthritis Patients Prevent the Inflammatory Activation of Macrophages
Rhys, H. I., Dell’Accio, F., Pitzalis, C., Moore, A., Norling, L. V., & Perretti, M. (2018) · EBioMedicine · doi:10.1016/j.ebiom.2018.02.003 · Cited by 113 · see citing works
Differential expression of the granzymes A, K and M and perforin in human peripheral blood lymphocytes
Bade, B., Boettcher, H. E., Lohrmann, J., Hink-Schauer, C., Bratke, K., Jenne, D. E., Virchow, J. C., Jr., & Luttmann, W. (2005) · International Immunology · doi:10.1093/intimm/dxh320 · Cited by 91 · cited 1× · see citing works
“CD56CD16 NK cells exhibited high expression of cytotoxic effector genes including perforin (PRF1) and most granzyme (GZMB, GZMA, and GZMH) except GZMK, which was instead exclusively expressed in CD56CD16 NK cells.(35) CD56CD16 NK cells expressed various cytokine genes such as IL18.”
Background
Human AML activates the aryl hydrocarbon receptor pathway to impair NK cell development and function
Scoville, S. D., Nalin, A. P., Chen, L., Chen, L., Zhang, M. H., McConnell, K. K., Casas, S. B., Ernst, G., Traboulsi, A. A.-R., Hashi, N. J., et al. (2018) · Blood · doi:10.1182/blood-2018-03-838474 · Cited by 84 · cited 2× · see citing works
“Such hypomaturation stage of NK cells has been associated with the reduction of overall survival and relapse-free survival of patients with AML.43,44 Compared with other NK cell populations, these CD56brightCD16hi cells exhibited distinctive phenotypic and functional shifts in terms of their extremely low activating a…”
Result
Alterations of NK Cell Phenotype in the Disease Course of Multiple Myeloma
Pazina, T., Macfarlane, A. W., Bernabei, L. L., Dulaimi, E., Kotcher, R. E., Yam, C., Bezman, N., Robbins, M. D. H., Ross, E. A., Campbell, K. S., et al. (2021) · Cancers · doi:10.3390/cancers13020226 · Cited by 72 · see citing works
Natural Killer Defective Maturation Is Associated with Adverse Clinical Outcome in Patients with Acute Myeloid Leukemia
Chrétien, A.-S., Fauriat, C., Orlanducci, F., Galseran, C., Rey, J., Bouvier, G., Gautherot, E., Granjeaud, S., Hamel‐Broza, J., Demerle, C., et al. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00573 · Cited by 69 · cited 2× · see citing works
“Such hypomaturation stage of NK cells has been associated with the reduction of overall survival and relapse-free survival of patients with AML.43,44 Compared with other NK cell populations, these CD56brightCD16hi cells exhibited distinctive phenotypic and functional shifts in terms of their extremely low activating a…”
Result
Human Cytomegalovirus Antigen Presentation by HLA-DR+ NKG2C+ Adaptive NK Cells Specifically Activates Polyfunctional Effector Memory CD4+ T Lymphocytes
Costa-García, M., Ataya, M., Moraru, M., Vilches, C., López‐Botet, M., & Muntasell, A. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00687 · Cited by 64 · see citing works
T-Cell Ig and ITIM Domain Regulates Natural Killer Cell Activation in Murine Acute Viral Hepatitis
Bi, J., Zhang, Q., Liang, D., Xiong, L., Wei, H., Sun, R., & Tian, Z. (2013) · Hepatology · doi:10.1002/hep.26968 · Cited by 57 · cited 1× · see citing works
“By contrast, TIGIT contributes to suppressing NK cellmediated immune responses as an inhibitory receptor.(28,69,70) Furthermore, in TCGA datasets, the abundance of LAMP3 DCs was correlated with CD56CD16 NK cells (Figures 6I, S6I, and S6J).”
Background
Single-cell transcriptomics reveal a unique memory-like NK cell subset that accumulates with ageing and correlates with disease severity in COVID-19
Guo, C., Wu, M., Huang, B., Zhao, R., Jin, L., Fu, B., Wang, P., Wang, D., Zheng, M., Fang, J., et al. (2022) · Genome Medicine · doi:10.1186/s13073-022-01049-3 · Cited by 54 · see citing works
Circulating and Tumor-Infiltrating NK Cells From Clear Cell Renal Cell Carcinoma Patients Exhibit a Predominantly Inhibitory Phenotype Characterized by Overexpression of CD85j, CD45, CD48 and PD-1
Ziblat, A., Iraolagoitia, X. L. R., Núñez, S. Y., Torres, N. I., Secchiari, F., Sierra, J. M., Spallanzani, R. G., Rovegno, A. R., Secin, F. P., Fuertes, M. B., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.681615 · Cited by 31 · see citing works
Impaired intratumoral natural killer cell function in head and neck carcinoma
Mele, D., Pessino, G., Trisolini, G., Luchena, A., Benazzo, M., Morbini, P., Mantovani, S., Oliviero, B., Mondelli, M., & Varchetta, S. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.997806 · Cited by 23 · see citing works
Natural killer cells and cytotoxic T lymphocytes are required to clear solid tumor in a patient-derived xenograft
Le, D. T., Huynh, T. R., Burt, B. M., Buren, G. V., Abeynaike, S. A., Zalfa, C., Nikzad, R., Kheradmand, F., Tyner, J. J., & Paust, S. (2021) · JCI Insight · doi:10.1172/jci.insight.140116 · Cited by 18 · see citing works
Downregulation of CD16 Surface Expression on NK Cells Is a Favorable Prognostic Factor in Acute Myeloid Leukemia
Wang, H., Zhang, X., Wald, D. N., Gong, S., Wang, W., & Wang, J. (2022) · Blood · doi:10.1182/blood-2022-168947 · Cited by 3 · see citing works

Flagged first, then by citations

Sorted by citations

Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19+ B cell tumors: a phase 1/2 trial
Marin, D., Li, Y., Başar, R., Rafei, H., Daher, M., Dou, J., Mohanty, V., Dede, M., Nieto, Y., Uprety, N., et al. (2024) · Nature Medicine · doi:10.1038/s41591-023-02785-8 · Cited by 458 · see citing works
“This pattern mirrors the stress response observed in T cells in the context of immunotherapy resistance 34 and the poor cytotoxicity seen in tumor-associated NK cells in a recent pan-cancer single-cell atlas of human NK cells 28 .”
BackgroundMethod
Natural killer cell therapies
Vivier, É., Rebuffet, L., Narni-Mancinelli, É., Cornen, S., Igarashi, R., & Fantin, V. R. (2024) · Nature · doi:10.1038/s41586-023-06945-1 · Cited by 481 · see citing works
“…cells characterized by reduced cytotoxicity and high expression of stress-associated proteins ( DNAJB1 and HSP gene family), inhibitory MHC-class-I-specific receptors (members of the KIR family) and several transcription factors that control the fitness of NK cells such as NR4A1, EGR3 and KLF6 29 .”
High-dimensional single-cell analysis of human natural killer cell heterogeneity
Rebuffet, L., Melsen, J. E., Escalière, B., Basurto-Lozada, D., Bhandoola, A., Björkström, N. K., Bryceson, Y. T., Castriconi, R., Cichocki, F. M., Colonna, M., et al. (2024) · Nature Immunology · doi:10.1038/s41590-024-01883-0 · Cited by 288 · see citing works
“We then confirmed the robustness of the classification of human blood NK cells into the NK1, NK2 and NK3 clusters by applying the derived transcriptional signatures to blood NK cells from other available datasets 11 (Extended Data Figs.”
Metabolic reprogramming and therapeutic resistance in primary and metastatic breast cancer
Liu, S., Zhang, X., Wang, W., Li, X., Sun, X., Zhao, Y., Wang, Q., Li, Y., Hu, F., & Ren, H. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02165-x · Cited by 279 · see citing works
Pan-cancer single-cell dissection reveals phenotypically distinct B cell subtypes
Yu, Y., Chen, X., Pan, J., Ning, H., Zhang, Y., Bo, Y., Ren, X., Li, J., Qin, S., Wang, D., et al. (2024) · Cell · doi:10.1016/j.cell.2024.06.038 · Cited by 219 · see citing works
Evolution of myeloid-mediated immunotherapy resistance in prostate cancer
Lyu, A., Fan, Z., Clark, M., Lea, A., Luong, D., Setayesh, A., Starzinski, A., Wolters, R. M., Arias-Badia, M., Allaire, K., et al. (2024) · Nature · doi:10.1038/s41586-024-08290-3 · Cited by 204 · see citing works
Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity
Dean, I., Lee, C. Y. C., Tuong, Z. K., Li, Z., Tibbitt, C. A., Willis, C., Gaspal, F., Kennedy, B. C., Matei‐Rascu, V., Fiancette, R., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-44789-z · Cited by 192 · see citing works
Dendritic cell maturation in cancer
Moon, C. Y., Belabed, M., Park, M. D., Mattiuz, R., Puleston, D. J., & Mérad, M. (2025) · Nature reviews. Cancer · doi:10.1038/s41568-024-00787-3 · Cited by 186 · see citing works
A single-cell atlas reveals immune heterogeneity in anti-PD-1-treated non-small cell lung cancer
Liu, Z., Yang, Z., Wu, J., Zhang, W., Sun, Y., Zhang, C., Bai, G., Li, Y., Fan, H., Chen, Y., et al. (2025) · Cell · doi:10.1016/j.cell.2025.03.018 · Cited by 166 · see citing works
Integrative single-cell analysis of human colorectal cancer reveals patient stratification with distinct immune evasion mechanisms
Chu, X., Li, X., Zhang, Y., Dang, G., Miao, Y., Xu, W., Wang, J., Zhang, Z., & Cheng, S. (2024) · Nature Cancer · doi:10.1038/s43018-024-00807-z · Cited by 163 · see citing works
“8e), consistent with what was reported in hepatocellular carcinoma 46 .”
Pan-cancer profiling of tumor-infiltrating natural killer cells through transcriptional reference mapping
Netskar, H., Pfefferle, A., Goodridge, J. P., Sohlberg, E., Dufva, O., Teichmann, S. A., Brownlie, D., Michaëlsson, J., Marquardt, N., Clancy, T., et al. (2024) · Nature Immunology · doi:10.1038/s41590-024-01884-z · Cited by 112 · see citing works
“Using a pan-cancer, single-cell atlas approach, Tang et al. 16 identified a tumor-enriched dysfunctional CD56 dim CD16 hi NK cell population interacting with LAMP3 + dendritic cells in the TME.”
Consensus, debate, and prospective on pancreatic cancer treatments
Wang, J., Yang, J., Narang, A. K., He, J., Wolfgang, C. L., Li, K., & Zheng, L. (2024) · Journal of Hematology & Oncology · doi:10.1186/s13045-024-01613-x · Cited by 99 · see citing works
Circulating NK cells establish tissue residency upon acute infection of skin and mediate accelerated effector responses to secondary infection
Torcellan, T., Friedrich, C., Doucet-Ladevèze, R., Ossner, T., Solé, V. V., Riedmann, S., Ugur, M., Imdahl, F., Rosshart, S. P., Arnold, S. J., et al. (2023) · Immunity · doi:10.1016/j.immuni.2023.11.018 · Cited by 95 · see citing works
Tumour-retained activated CCR7+ dendritic cells are heterogeneous and regulate local anti-tumour cytolytic activity
Lee, C. Y. C., Kennedy, B. C., Richoz, N., Dean, I., Tuong, Z. K., Gaspal, F., Li, Z., Willis, C., Hasegawa, T., Whiteside, S. K., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-44787-1 · Cited by 78 · see citing works
“Recent studies also report that CCR7 + DCs may engage other immune cells in tumours, including CXCL13 + CD4 + T cells, regulatory T cells and NK cells 38,50 – 52 , and may reside in TLS 12,15 .”
Background
Machine learning identifies TIME subtypes linking EGFR mutations and immune states in lung adenocarcinoma
Gong, Z., Du, M., Li, Y., Ye, B., Huang, Y., Gong, H., Wang, W., Chen, L., Ding, Z., & Zhang, P. (2025) · npj Digital Medicine · doi:10.1038/s41746-025-02172-2 · Cited by 73 · see citing works
“Although accumulating evidence suggests that NK cells, as non-speci ﬁ c immune effectors, play animportantrole inregulating thetumor microenvironment and antitumor immunity, their molecular markers and prognostic signi ﬁ cance remain insuf ﬁ ciently characterized 30 – 32 .”
Advances and applications in single-cell and spatial genomics
Wang, J., Ye, F., Chai, H., Jiang, Y., Wang, T., Ran, X., Xia, Q., Xu, Z., Fu, Y., Zhang, G., et al. (2024) · Science China Life Sciences · doi:10.1007/s11427-024-2770-x · Cited by 69 · see citing works
Cross-tissue multicellular coordination and its rewiring in cancer
Shi, Q., Chen, Y., Li, Y., Qin, S., Yang, Y., Gao, Y., Zhu, L., Wang, D., & Zhang, Z. (2025) · Nature · doi:10.1038/s41586-025-09053-4 · Cited by 72 · see citing works
Considerations for building and using integrated single-cell atlases
Hrovatin, K., Sikkema, L., Shitov, V. A., Heimberg, G., Shulman, M., Oliver, A. J., Mueller, M. F., Ibarra, I. L., Wang, H., Ramírez-Suástegui, C., et al. (2024) · Nature Methods · doi:10.1038/s41592-024-02532-y · Cited by 67 · see citing works
Single-cell resolution spatial analysis of antigen-presenting cancer-associated fibroblast niches
Chen, X., Zhou, Z., Xie, L., Qiao, K., Jia, Y., Liu, S., Yazgan, Z., Rossi, F., Liu, Y., Zhang, B., et al. (2025) · Cancer Cell · doi:10.1016/j.ccell.2025.09.001 · Cited by 63 · see citing works
CREM is a regulatory checkpoint of CAR and IL-15 signalling in NK cells
Rafei, H., Başar, R., Acharya, S., Hsu, Y.-S., Liu, P., Zhang, D., Bohn, T., Liang, Q., Mohanty, V., Upadhyay, R., et al. (2025) · Nature · doi:10.1038/s41586-025-09087-8 · Cited by 62 · see citing works
“Recent studies have reported distinct subsets of NK cells with high CREM expression 8,48 , although the functional implications were not explored.”
Engineered natural killer cells for cancer therapy
Biederstädt, A., & Rezvani, K. (2025) · Cancer Cell · doi:10.1016/j.ccell.2025.09.013 · Cited by 59 · see citing works
Tumor-associated neutrophils upregulate Nectin2 expression, creating the immunosuppressive microenvironment in pancreatic ductal adenocarcinoma
Luo, H., Ikenaga, N., Nakata, K., Higashijima, N., Zhong, P., Kubo, A., Wu, C.-Y., Tsutsumi, C., Shimada, Y., Hayashi, M., et al. (2024) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-024-03178-6 · Cited by 56 · see citing works
“The advent of single-cell analysis has provided insights into the landscape and dynamics of immune cell populations within cancer tissues [16, 17].”
Background
Spatiotemporal metabolomic approaches to the cancer-immunity panorama: a methodological perspective
Xiao, Y., Li, Y., & Zhao, H. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02113-9 · Cited by 59 · see citing works
Genome-wide CRISPR screens identify critical targets to enhance CAR-NK cell antitumor potency
Biederstädt, A., Başar, R., Park, J.-M., Uprety, N., Shrestha, R., Silva, F. R., Dede, M., Watts, J., Acharya, S., Xiong, D., et al. (2025) · Cancer Cell · doi:10.1016/j.ccell.2025.07.021 · Cited by 55 · see citing works
Interactions between LAMP3+ dendritic cells and T-cell subpopulations promote immune evasion in papillary thyroid carcinoma
Wang, Z., Ji, X., Zhang, Y., Yang, F., Su, H., Zhang, H., Li, Z., Zhang, W., & Sun, W. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-008983 · Cited by 51 · see citing works
Pan-cancer human brain metastases atlas at single-cell resolution
Xing, X., Zhong, J., Biermann, J., Duan, H., Zhang, X., Shi, Y., Gao, Y., He, K., Zhai, D., Luo, F., et al. (2025) · Cancer Cell · doi:10.1016/j.ccell.2025.03.025 · Cited by 55 · see citing works
Immunocytes in the tumor microenvironment: recent updates and interconnections
Yu, J., Fu, L., Wu, R., Che, L., Liu, G., Ran, Q., Xia, Z., Liang, X., & Zhao, G. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1517959 · Cited by 52 · see citing works
“Notably, TaNK cells express higher levels of inhibitory receptors (e.g., KIRs) and lower levels of cytotoxic markers, suggesting a potentially “ dysfunctional ” phenotype with impaired tumor-killing capacity (100).”
The emerging role of dendritic cells in the tumor microenvironment: from antigen presentation to targeted immunotherapy
Xie, Z., Fang, Y., Zhang, X., Fang, Y., Li, R., Guo, Y., Yang, Y., Yang, S., & Song, L. (2025) · Cell Death and Disease · doi:10.1038/s41419-025-08180-0 · Cited by 54 · see citing works
“CD56 dim CD16 hi NK cells exert potent cytotoxicity via perforin and granzyme B secretion, whereas CD56 bright CD16 lo NK cells produce substantial amounts of IFN-γ and other cytokines that are crucial for immunomodulation [75].”
Increased Siglec-9/Siglec-9L interactions on NK cells predict poor HCC prognosis and present a targetable checkpoint for immunotherapy
Xiao, R., Tian, Y., Zhang, J., Li, N., Qi, M., Liu, L., Wang, J., Li, Z., Zhang, J., Zhao, F., et al. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.01.028 · Cited by 42 · see citing works
Pan-cancer integrative analyses dissect the remodeling of endothelial cells in human cancers
Li, J., Wang, D., Tang, F., Ling, X., Zhang, W., & Zhang, Z. (2024) · National Science Review · doi:10.1093/nsr/nwae231 · Cited by 42 · see citing works
“Single-cell RNA-seq (scRNA-seq) technologies empower the high-resolution characterization of cellular heterogeneity in the TME, bringing new opportunities to i l luminate the spectrum of TECs [18 ,22 ,23 ].”
Background
The spatial landscape of cancer hallmarks reveals patterns of tumor ecological dynamics and drug sensitivity
Sibai, M., Cervilla, S., Grases, D., Musulén, E., Lazcano, R., Mo, C.-K., Dávalos, V., Fortian, A., Bernat‐Peguera, A., Romeo, M., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2024.115229 · Cited by 42 · see citing works
TGF-β signalling limits effector function capacity of NK cell anti-tumour immunity in human bladder cancer
Wong, J., McCulloch, T., Alim, L., Omer, N., Mehdi, A. M., Tuong, Z., Bonfim-Melo, A., Chung, E., Nicol, A., Simpson, F., et al. (2024) · EBioMedicine · doi:10.1016/j.ebiom.2024.105176 · Cited by 36 · see citing works
“To validate these NK signatures, we applied the gene-sets to a pan-cancer human NK cell atlas developed by Tang et al., 2023 35 (Supplementary Figure S6B).”
Influential
Cancer-Associated Fibroblasts Serve as Decoys to Suppress NK Cell Anticancer Cytotoxicity in Breast Cancer
Ben‐Shmuel, A., Gruper, Y., Halperin, C., Levi-Galibov, O., Rosenberg-Fogler, H., Barki, D., Carradori, G., Stein, Y., Yagel, G., Naumova, M., et al. (2025) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-0131 · Cited by 49 · see citing works
Sialic acid and Siglec receptors in tumor immunity and immunotherapy
Mantuano, N. R., & Laubli, H. P. (2024) · Seminars in Immunology · doi:10.1016/j.smim.2024.101893 · Cited by 40 · see citing works
The Curated Cancer Cell Atlas provides a comprehensive characterization of tumors at single-cell resolution
Tyler, M., Gavish, A., Barbolin, C., Tschernichovsky, R., Hoefflin, R., Mints, M., Puram, S. V., & Tirosh, I. (2025) · Nature Cancer · doi:10.1038/s43018-025-00957-8 · Cited by 47 · see citing works
Cellular senescence and neurodegeneration
Holloway, K., Neherin, K., Dam, K. U., & Zhang, H. (2023) · Human Genetics · doi:10.1007/s00439-023-02565-x · Cited by 40 · see citing works
scImmOmics: a manually curated resource of single-cell multi-omics immune data
Li, Y., Zhou, L., Qian, F., Fang, Q.-L., Yu, Z., Cui, T., Dong, F.-J., Cai, F.-H., Yu, T., Li, L., et al. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae985 · Cited by 35 · see citing works
Single‐Cell Analysis Reveals Malignant Cells Reshape the Cellular Landscape and Foster an Immunosuppressive Microenvironment of Extranodal NK/T‐Cell Lymphoma
Li, Y., Luo, C., Jiang, J., He, S., Liu, Y., Yan, W., Xia, Y., Cui, Q., Huang, Y., Lim, J. Q., et al. (2023) · Advanced Science · doi:10.1002/advs.202303913 · Cited by 35 · see citing works
Human NK cells and cancer
Cantoni, C., Falco, M., Vitale, M., Pietra, G., Munari, E., Pende, D., Mingari, M. C., Sivori, S., & Moretta, L. (2024) · OncoImmunology · doi:10.1080/2162402x.2024.2378520 · Cited by 35 · see citing works
“17,21 In addition, the development of advanced single-cell technologies, such as scRNA-seq and CITE (Cellular Indexing of Transcriptomes and Epitopes)-seq, has accelerated the dissection of NK cell subset heterogeneity, revealing an intricate and nuanced NK cell landscape as well as different…”
Background
Spatiotemporal analyses of the pan-cancer single-cell landscape reveal widespread profibrotic ecotypes associated with tumor immunity
Han, Y., Zhang, L., Sun, D., Cao, G., Wang, Y., Yue, J., Hu, J., Dong, Z., Li, F., Li, T., et al. (2025) · Nature Cancer · doi:10.1038/s43018-025-01039-5 · Cited by 37 · see citing works
Cytotoxic NK Cells Impede Response to Checkpoint Immunotherapy in Melanoma with an Immune-Excluded Phenotype
Poźniak, J., Roda, N., Landeloos, E., Antoranz, A., Herck, Y. V., Visscher, A. D., Demaerel, P. G., Vanwynsberghe, L., Declercq, J., Gkemisis, C., et al. (2025) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-1208 · Cited by 32 · see citing works
“In keeping with this, three recent studies described an association between NK cells and lack of response to immunotherapy in different cancer types (6–8).”
Influential
Single-cell and spatial transcriptomics profile the interaction of SPP1+ macrophages and FAP+ fibroblasts in non-small cell lung cancer
Xiao, M., Deng, Y., Guo, H., Ren, Z., He, Y., Ren, X., Huang, L., Zhang, W., Chen, H., Yang, S., et al. (2025) · Translational Lung Cancer Research · doi:10.21037/tlcr-2025-244 · Cited by 30 · see citing works
Non-invasive profiling of the tumour microenvironment with spatial ecotypes
Zhang, W., Brown, E. L., Usmani, A., Earland, N. J., Kang, M., Olelewe, C., Viswanathan, A., Chauhan, P. S., Steen, C. B., Jeon, H. S., et al. (2026) · Nature · doi:10.1038/s41586-026-10452-4 · Cited by 34 · see citing works
Urine scRNAseq reveals new insights into the bladder tumor immune microenvironment
Tran, M. A., Youssef, D., Shroff, S., Chowhan, D., Beaumont, K. G., Sebra, R., Mehrazin, R., Wiklund, P. N., Lin, J. J., Horowitz, A., et al. (2024) · The Journal of Experimental Medicine · doi:10.1084/jem.20240045 · Cited by 30 · see citing works
The Spatial Organization of cDC1 with CD8+ T Cells is Critical for the Response to Immune Checkpoint Inhibitors in Patients with Melanoma
Gobbini, É., Hubert, M., Doffin, A., Eberhardt, A., Hermet, L., Li, D., Duplouye, P., Barrin, S., Berthet, J., Benboubker, V., et al. (2025) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-24-0421 · Cited by 31 · see citing works
Immunoregulatory mechanisms of the arachidonic acid pathway in cancer
Tredicine, M., Mucci, M., Recchiuti, A., & Mattoscio, D. (2025) · FEBS Letters · doi:10.1002/1873-3468.70013 · Cited by 30 · see citing works
Mitochondrial dynamics and metabolic attributes regulate function of natural killer cell and infiltration in tumor microenvironment modulating disease progression
Ghosh, S., Dutta, R. K., Goswami, D., Ghatak, D., & De, R. (2025) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2025.189471 · Cited by 30 · see citing works
Paracrine Orchestration of Tumor Microenvironment Remodeling Induced by GLO1 Potentiates Lymph Node Metastasis in Breast Cancer
Xie, J., Liu, W., Deng, X., Wang, H., Ou, X., An, X., Situ, M., Yang, A., Peng, C., He, R., et al. (2025) · Advanced Science · doi:10.1002/advs.202500722 · Cited by 29 · see citing works
Reprogramming natural killer cells in the tumor microenvironment: Challenges and therapeutic opportunities
Ma, W., Morris, S., & Jamieson, C. H. M. (2025) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2025.10.001 · Cited by 27 · see citing works
“Single-cell RNA sequencing coupled with spatial profiling has further shown that such immunoregulatory NK populations preferentially localize within T cell-rich tumor regions, positioning them as key modulators of T cell responses in immune-inflamed tumors [56,57].”
Single-cell multi-omic landscape reveals anatomical-specific immune features in adult and pediatric sepsis
Ye, Q., Lai, X., Liu, Y., Zhang, Z., Fu, Y.-Q., Luo, J., Liu, C., Duan, J., Ding, H., Liu, Y., et al. (2025) · Nature Immunology · doi:10.1038/s41590-025-02345-x · Cited by 31 · see citing works
“In tumors, NR4A2, along with NR4A1 and NR4A3, has been shown to drive exhaustion and limit effector functions in chimeric antigen receptor T cells 27,28 , whereas in tumor-associated NK cells, NR4A2 expression is linked to reduced cytotoxic activity and a dysfunctional state 43 .”
Single-cell RNA sequencing in cancer research: discovering novel biomarkers and therapeutic targets for immune checkpoint blockade
Sun, B., Xun, Z., Zhang, N., Liu, K., Chen, X., & Zhao, H. (2023) · Cancer Cell International · doi:10.1186/s12935-023-03158-4 · Cited by 27 · see citing works
“In a pan-cancer scRNA-seq study [122], CD56 dim CD16 hi c6-DNAJB1 NK cells were designated as tumor-associated NK (TaNK) cells, which were enriched in tumors and exhibited impaired cytotoxicity, indicative of a terminal state.”
Background
Influenza A virus dissemination and infection leads to tissue resident cell injury and dysfunction in viral sepsis
Zheng, Y., He, D., Zuo, W., Wang, W., Wu, K., Wu, H., Yuan, Y., Huang, Y.-J., Li, H., Lu, Y., et al. (2025) · EBioMedicine · doi:10.1016/j.ebiom.2025.105738 · Cited by 29 · see citing works
“37 The de ﬁ nition of “ viral load ” in a cell is the percentage of UMIs mapped to one of eight viral segments in the total mapped UMIs.”
STING in cancer immunoediting: Modeling tumor-immune dynamics throughout cancer development
Zhang, X., Chen, Y., Liu, X., Li, G., Zhang, S., Zhang, Q., Cui, Z., Qin, M., Simon, H., Terzić, J., et al. (2025) · Cancer Letters · doi:10.1016/j.canlet.2024.217410 · Cited by 27 · see citing works
Pan‐cancer analysis shapes the understanding of cancer biology and medicine
Cen, X., Lan, Y., Zou, J., Chen, R., Hu, C., Tong, Y., Zhang, C., Chen, J., Wang, Y., Zhou, R., et al. (2025) · 癌症：英文版 · doi:10.1002/cac2.70008 · Cited by 27 · see citing works
“Additionally, TaNKs and iCAF were significantly correlated with resistance to immunotherapy [46, 134].”
Single-cell and spatial transcriptomics reveal alterations in trophoblasts at invasion sites and disturbed myometrial immune microenvironment in placenta accreta spectrum disorders
Ji, K., Chen, Y., Pan, X., Chen, L., Wang, X., Wen, B., Bao, J., Zhong, J., Lv, Z., Zheng, Z., et al. (2024) · Biomarker Research · doi:10.1186/s40364-024-00598-6 · Cited by 24 · see citing works
“…cell (EC) (VWF) [35], lymphatic endothelial cell (LEC) (TFF3) [35]; immune cells: T cell (CD3D) [19, 35], B cell (CD79A) [19, 35], NK cell (KLRB1) [51], monocyte (CD14) [35, 52], mast cell (TPSB2) [35]; cells in cell cycle (cycling) (TOP2A) [53] and red blood cell (RBC) (HBA2) [54] (Fig.”
Background
MAZ-mediated tumor progression and immune evasion in hormone receptor-positive breast cancer: Targeting tumor microenvironment and PCLAF+ subtype-specific therapy
Ni, G., Sun, Y., Jia, H., Xiahou, Z., Li, Y., Zhao, F. Q., & Zang, H. (2025) · Translational Oncology · doi:10.1016/j.tranon.2025.102280 · Cited by 24 · see citing works
Multi-omic analysis of gallbladder cancer identifies distinct tumor microenvironments associated with disease progression
Zhou, T., Wu, Y., Li, S., Qiu, X., Liu, E., Xie, Z., Shi, X., Zhang, Y., Ma, G., Guo, W., et al. (2025) · Nature Genetics · doi:10.1038/s41588-025-02236-9 · Cited by 25 · see citing works
NK cells with adhesion defects and reduced cytotoxic functions are associated with a poor prognosis in multiple myeloma
Blanquart, E., Ekren, R., Rigaud, B., Joubert, M.-V., Baylot, V., Daunes, H., Cuisinier, M., Villard, M., Carrié, N., Mazzotti, C., et al. (2024) · Blood · doi:10.1182/blood.2023023529 · Cited by 22 · see citing works
Tissue-colonizing disseminated tumor cells secrete prostaglandin E2 to promote NK cell dysfunction and evade anti-metastatic immunity
Pedde, A., Kim, H., Donakonda, S., Baumann, T., Bayerl, F., Meiser, P., Hirschberger, A., Klement, C., Grassmann, S. A., Öllinger, R., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114855 · Cited by 22 · see citing works
CancerSCEM 2.0: an updated data resource of single-cell expression map across various human cancers
Zeng, J., Nie, Z., Shang, Y., Mai, J., Zhang, Y., Yang, Y., Xu, C., Zhao, J., Fan, Z., & Xiao, J. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae954 · Cited by 24 · see citing works
Single-cell meta-analysis of T cells reveals clonal dynamics of response to checkpoint immunotherapy
Shorer, O., Pinhasi, A., & Yizhak, K. (2024) · bioRxiv · doi:10.1016/j.xgen.2025.100842 · Cited by 21 · see citing works
“…in ICI-treated patients with Richter syndrome 41 and to the revival of pre-existing ZNF683 + clones in patients with HNSCC responding to ICI treatment, 42 this ﬁnding emphasizes the importance of the contextual co-expression of genes in relation to clinical outcome, as well as differences…”
Machine Learning Integration with Single-Cell Transcriptome Sequencing Datasets Reveals the Impact of Tumor-Associated Neutrophils on the Immune Microenvironment and Immunotherapy Outcomes in Gastric Cancer
Zhang, J., Zhang, M., Lou, J., Wu, L., Zhang, S., Liu, X., Ke, Y., Zhao, S., Song, Z., Bai, X., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252312715 · Cited by 20 · see citing works
Single-cell RNA sequencing reveals anti-tumor potency of CD56+ NK cells and CD8+ T cells in humanized mice via PD-1 and TIGIT co-targeting
Liu, W.-N., Harden, S., Tan, S. L. W., Tan, R. J. R., Fong, S., Tan, S. Y., Liu, M., Karnik, I., Shuen, T. W. H., Toh, H. C., et al. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.09.025 · Cited by 21 · see citing works
“34,35 As depicted in Figure S6, these markers were highly expressed in our identi ﬁ ed NK cell clusters.”
Single-cell multi-omics analysis reveals candidate therapeutic drugs and key transcription factor specifically for the mesenchymal subtype of glioblastoma
Yang, Y., Liu, Z., Wei, Y., He, S., Gu, A., Li, Z., Li, J., Xu, Z., & Cen, B. (2024) · Cell & Bioscience · doi:10.1186/s13578-024-01332-3 · Cited by 19 · see citing works
Harnessing natural killer cell effector function against cancer
Blunt, M. D., & Khakoo, S. I. (2023) · Immunotherapy Advances · doi:10.1093/immadv/ltad031 · Cited by 19 · see citing works
“Thus in some solid organ cancers, CD56dim CD16high HSP40+ tumour-asssociated NK cells display a dysfunctional state with reduced perforin and granzyme B [29].”
The Problem with Syngeneic Mouse Tumor Models
Lönberg, N. (2025) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-24-1046 · Cited by 20 · see citing works
Pan-Cancer Analyses Refine the Single-Cell Portrait of Tumor-Infiltrating Dendritic Cells
Ma, T., Chu, X., Wang, J., Li, X., Zhang, Y., Tong, D., Xu, W., Dang, G., Qi, L., Miao, Y., et al. (2025) · Cancer Research · doi:10.1158/0008-5472.can-24-3595 · Cited by 17 · see citing works
Advancing immunotherapy for melanoma: the critical role of single-cell analysis in identifying predictive biomarkers
He, R., Lu, J., Feng, J., Lu, Z., Shen, K., Xu, K., Luo, H., Yang, G., Chi, H., & Huang, S. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1435187 · Cited by 17 · see citing works
“Additionally, single-cell analysis can elucidate changes in systemic immunity during tumor progression; researchers identi ﬁ ed an adaptive NK cell subgroup characterized by upregulation of speci ﬁ c pro-in ﬂ ammatory cytokines and MHC class II genes in the peripheral blood of cancer patients (52).”
Background
Unveiling novel insights in acute myeloid leukemia through single-cell RNA sequencing
Zhou, J., & Chng, W. J. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1365330 · Cited by 16 · see citing works
Targeting macrophage-derived SPP1 enhances CD8 T cell infiltration via ROS-DNA fragment/cGAS-STING/STAT1-mediated CXCL9/10 in tumor microenvironment
Wang, J., Shi, Y., Gao, Y., Zhu, N., Liu, Y., Zhang, Y., Chen, X., & Yang, R. (2026) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2025-013697 · Cited by 16 · see citing works
Radiofrequency radiation reshapes tumor immune microenvironment into antitumor phenotype in pulmonary metastatic melanoma by inducing active transformation of tumor-infiltrating CD8+ T and NK cells
Jiao, J.-Z., Zhang, Y., Zhang, W., He, M., Meng, M., Liu, T., Ma, Q., Xu, Y., Gao, P., Chen, C., et al. (2024) · Acta Pharmacologica Sinica · doi:10.1038/s41401-024-01260-5 · Cited by 15 · see citing works
“However, NK cells exhibit tissue heterogeneity across cancer types [34].”
Background
The stress response regulator HSF1 modulates natural killer cell anti-tumour immunity
Hockemeyer, K., Sakellaropoulos, T., Chen, X., Ivashkiv, O., Sirenko, M., Zhou, H., Gambi, G., Battistello, E., Avrampou, K., Sun, Z., et al. (2024) · Nature Cell Biology · doi:10.1038/s41556-024-01490-z · Cited by 16 · see citing works
“For analysis of the pan-cancer atlas of human NK cells 39 , analysis was performed using Seurat (v.4.3.0.1) in R v.4.2.2 and Scanpy v.1.6.0 in Python v.3.7.8.”
Influential
The role of long non‐coding RNA Maternally Expressed Gene 3 in cancer‐associated fibroblasts at single cell pan‐cancer level
Zhou, T., Yan, H., Deng, Y., Zhu, Y., Xia, X., Wu, W., Zhang, W., Chen, H., Hu, J., Zhou, Z., et al. (2024) · Interdisciplinary medicine · doi:10.1002/inmd.20240018 · Cited by 17 · see citing works
Resting natural killer cells promote the progress of colon cancer liver metastasis by elevating tumor-derived stem cell factorPreprint
Mao, C., Chen, Y., Xing, D., Zhang, T., Lin, Y., Long, C., Yu, J., Luo, Y., Ming, T., Mei, D., et al. (2024) · eLife · doi:10.7554/elife.97201 · Cited by 16 · see citing works
Single-cell transcriptomic insights into chemotherapy-induced remodeling of the osteosarcoma tumor microenvironment
Zheng, X., Wu, W., Zhao, Z., Zhang, X., & Yu, S. (2024) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-024-05787-2 · Cited by 15 · see citing works
“6D, E, F) (Tang et al. 2023).”
Single-cell transcriptomics reveals immunosuppressive microenvironment and highlights tumor-promoting macrophage cells in Glioblastoma
Cheng, H., Yan, Y., Zhang, B., Ma, Z., Fu, S., Ji, Z. L., Zou, Z., & Wang, Q. (2025) · PLoS ONE · doi:10.1371/journal.pone.0312764 · Cited by 16 · see citing works
“TaNK cells have been associated with poor patient outcomes and resistance to immunotherapy in different cancer types [39].”
BackgroundInfluential
Robust differentiation of NK cells from MSLN.CAR-IL-15–engineered human iPSCs with enhanced antitumor efficacy against solid tumors
Jiang, Q., Yu, W., Ma, J., Zhao, M., Zou, J., Mir, S. A., Zhang, J., Germain, R. N., & Hassan, R. (2025) · Science Advances · doi:10.1126/sciadv.adt9932 · Cited by 15 · see citing works
“The NK5 cluster was characterized by high expression of cell division genes, including STMN1 , RRM2 , and ZWINT , along with the tumor-infiltrating NK marker RGS1 ( 27 ), suggesting that they may correspond to the Ki67 + NK population observed in immunofluorescence imaging.”
Single-cell RNA sequencing reveals different cellular states in malignant cells and the tumor microenvironment in primary and metastatic ER-positive breast cancer
Ozmen, F., Ozmen, T. Y., Ors, A., Janghorban, M., Rames, M. J., Li, X., Doe, A. R., Behbod, F., Mills, G. B., & Mohammed, H. (2025) · npj Breast Cancer · doi:10.1038/s41523-025-00808-w · Cited by 16 · see citing works
“Afterintegration,NKcells,myeloidcells,Tcells,Bcells,and ﬁ broblasts werefurtherclassi ﬁ edusingthefollowingpubliclyavailablesingle-cellRNA seq datasets: NK cells (GSE212890) 115 , T, myeloid, and B cells (GSE169426) 116 , and ﬁ broblasts(GSE103322, GSE132465, GSE154778, and GSE212966) 86 .”
HMGB2 drives tumor progression and shapes the immunosuppressive microenvironment in hepatocellular carcinoma: insights from multi-omics analysis
Chen, Y., Meng, Z., & Xiang, Z. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1415435 · Cited by 15 · see citing works
“The comprehensive mapping of TME components in HCC is continuously evolving, encompassing T cells (15), neutrophils (16), NK cells (17), as well as various potentially signi ﬁ cant subsets and driver genes previously undiscovered, such as the function and clinical relevance of exhausted CD8+ T…”
Background
Redefining the tumor microenvironment with emerging therapeutic strategies
Xu, S., Li, X., & Ma, W. (2024) · Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics · doi:10.32604/or.2024.055161 · Cited by 15 · see citing works
“Recent studies using single-cell RNA sequencing have uncovered a range of cell types in the TME, highlighting the importance of treatment strategies [5 – 7].”
Background
Modulation of natural killer cell exhaustion in the lungs: the key components from lung microenvironment and lung tumor microenvironment
Zhang, H., Wang, J., & Li, F. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1286986 · Cited by 15 · see citing works
“Further transcriptomic feature analysis in this study has shown that a subset of tumor-associated NK cells is enriched in tumors and displays exhaustion features and impaired antitumor functions in multiple cancers, including lung cancer (58).”
Background
RAC1high NK cell-based immunotherapy in hepatocellular carcinoma via STAT3-NKG2D axis
Shi, X., Chen, W., Yin, Y., Cao, H., Wang, X., Jiang, W., Li, Q., Li, X., Yu, Y., & Wang, X. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.216909 · Cited by 14 · see citing works
HPK1 Dysregulation‐Associated NK Cell Dysfunction and Defective Expansion Promotes Metastatic Melanoma Progression
Choi, W. S., Kwon, H., Yi, E., Lee, H., Kim, J. M., Park, H. J., Choi, E. J., Choi, M. E., Sung, Y. H., Won, C. H., et al. (2024) · Advanced Science · doi:10.1002/advs.202400920 · Cited by 14 · see citing works
Progressive natural killer cell dysfunction in advanced-stage clear-cell renal cell carcinoma and association with clinical outcomes
Xu, W. V., Birch, G., Meliki, A., Moritz, V., Bharadwaj, M., Schindler, N. R., Labaki, C., Saliby, R. M., Dinh, K., Horst, J. T., et al. (2025) · ESMO Open · doi:10.1016/j.esmoop.2024.104105 · Cited by 14 · see citing works
Dual targeting of CDK4/6 and CDK7 augments tumor response and antitumor immunity in breast cancer models
Kim, S., Son, E., Park, H.-R., Kim, M., & Yang, H. W. (2025) · Journal of Clinical Investigation · doi:10.1172/jci188839 · Cited by 14 · see citing works
Single‐Cell and Spatial Omics: Methods and Applications
Cen, X., Huang, X., Deng, E., Gong, X., Tan, N., Ye, J. T., Wang, Y., Eils, R., Luo, Q., Li, Y., et al. (2026) · MedComm · doi:10.1002/mco2.70713 · Cited by 13 · see citing works
“…single-cell atlases encompassing more than 700 cases have delineated conserved and divergent immune, stromal, and malignant programs across tumors, identifying recurrent T cell exhaustion states [ 324 ], natural killer cell phenotypes [ 325 ], and cancer-associated B cell populations [ 326 ].”
Large-scale bulk and single-cell RNA sequencing combined with machine learning reveals glioblastoma-associated neutrophil heterogeneity and establishes a VEGFA+ neutrophil prognostic model
Yang, Y., Liu, Z., Wang, Z., Fu, X., Li, Z., Li, J., Xu, Z., & Cen, B. (2025) · Biology Direct · doi:10.1186/s13062-025-00640-z · Cited by 13 · see citing works
OR7A10 GPCR engineering boosts CAR-NK therapy against solid tumours
Yang, L., Renauer, P. A., Tang, K., Saskin, J., Zhou, L., Zou, C., Lee, S.-H., Fox, M. L., Johnson-Noya, S., Weiss, B., et al. (2026) · Nature · doi:10.1038/s41586-026-10149-8 · Cited by 12 · see citing works
“…subsets were each characterized by established NK cell markers from molecular and SCT studies of tumour-infiltrating NK cells, including those for proliferation ( MKI67 ), NK differentiation ( BATF3 ), IL32 , memory-like NK phenotype ( KLRC2 ), stress ( CREM ) and NK cell dysfunction ( EGR2 ) 74 .”
Advancing precision medicine in gliomas through single-cell sequencing: unveiling the complex tumor microenvironment
Li, J., Zhang, Y., Liang, C., Yan, X., Hui, X., & Liu, Q. (2024) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1396836 · Cited by 12 · see citing works
Multi-omics approaches for identifying the PANoptosis signature and prognostic model via a multimachine-learning computational framework for intrahepatic cholangiocarcinoma
Yu, Y., You, Y., Duan, Y., Kang, M., Zhou, B., Yang, J., Yin, K.-L., Ye, W., Xu, R., Wang, H., et al. (2025) · Hepatology · doi:10.1097/hep.0000000000001352 · Cited by 12 · see citing works
Targeting HMGB2 acts as dual immunomodulator by bolstering CD8 + T cell function and inhibiting tumor growth in hepatocellular carcinoma
Qu, W., Zhu, G., Yang, R., Chu, T.-H., Guan, Z.-Q., Huang, R., Tian, M., Jiang, X., Tao, C.-Y., Fang, Y., et al. (2025) · Science Advances · doi:10.1126/sciadv.ads8597 · Cited by 12 · see citing works
Pan-cancer profiling of tumor-infiltrating natural killer cells through transcriptional reference mappingPreprint
Netskar, H., Pfefferle, A., Goodridge, J. P., Sohlberg, E., Dufva, O., Teichmann, S. A., Clancy, T., Horowitz, A., & Malmberg, K. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.10.26.564050 · Cited by 12 · see citing works
“Using a pan-cancer single-cell atlas approach, Tang et al. 16 identified a tumor-enriched dysfunctional CD56 dim CD16 hi NK cell population interacting with LAMP3 + dendritic cells in the tumor microenvironment (TME).”
MethodResultInfluential
A perspective on integrating digital pathology, proteomics, clinical data and AI analytics in cancer research
Guedes, J., Woldmar, N., Szasz, A. M., Wieslander, E., Pawłowski, K., Horvatovich, P., Malm, J., Szadai, L., Németh, I. B., Marko-Varga, G., et al. (2025) · Journal of Proteomics · doi:10.1016/j.jprot.2025.105493 · Cited by 11 · see citing works
Nuclear mitochondrial acetyl-CoA acetyltransferase 1 orchestrates natural killer cell-dependent antitumor immunity in colorectal cancer
Chen, W., Liao, K., Chen, H., Xiao, Z.-X., Meng, Q., Liu, Z., Lu, Y., Sheng, H., Mo, H., Wu, Q.-N., et al. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02221-y · Cited by 11 · see citing works
“Considering that NK cells in the TME have been reported to exhibit different phenotypes, including dysfunctional states, 18,47 we examined NK cells isolated from orthotopic tumors and performed Smart-seq2 to ensure that the elevated tumor-in ﬁ ltrating NK cells induced by ACAT1 were activated.”
Engineering NK and T cells with metabolite-sensing receptors to target solid tumors
Kim, Y., Tsai, M. K., Sun, C., Laveroni, O., Akana, R. V., Frombach, K. R., & Jerby‐Arnon, L. (2026) · Nature Immunology · doi:10.1038/s41590-026-02473-y · Cited by 14 · see citing works
Overactivation of XBP1 in plasma cells implies worse survival through innate immunity in esophageal squamous cell carcinoma
Yin, Y., Wang, Y., Yu, X., Li, Y., Zhao, Y., & Liu, Z. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.217045 · Cited by 11 · see citing works
Innovative treatment of age-related hearing loss using MSCs and EVs with Apelin
Xu, S., Liu, D., Zhang, F., & Tian, Y. (2025) · Cell Biology and Toxicology · doi:10.1007/s10565-025-09988-4 · Cited by 12 · see citing works
The landscape of malignant transition: Unraveling cancer cell-of-origin and heterogeneous tissue microenvironment
Luo, R., Liu, J., Wang, T., Zhao, W., Wang, Y., Wen, J., Wang, H., Ding, S., & Zhou, X. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.217591 · Cited by 13 · see citing works
NKG7 is a Stable Marker of Cytotoxicity Across Immune Contexts and Within the Tumor Microenvironment
Turiello, R., Ng, S. S., Tan, E., van der Voort, G., Salim, N., Yong, M. C. R., Khassenova, M., Oldenburg, J., Rühl, H., Hasenauer, J., et al. (2025) · European Journal of Immunology · doi:10.1002/eji.202551885 · Cited by 11 · see citing works
Masters of adaptation: How cancer and immune cell plasticity mediates tumor progression
Rosenbaum, S. R., Fields, K. M., & Ford, H. L. (2025) · PLoS Biology · doi:10.1371/journal.pbio.3003301 · Cited by 12 · see citing works
“…analysis of patient samples across 24 cancer types, which demonstrated that NK cell heterogeneity was specific to tumor type and that tumor-infiltrating NK cells had reduced cytotoxic features compared to blood-derived NK cells [148], suggesting that NK cells shift their phenotype upon tumor entry.”

A Pan-Cancer Single-Cell Transcriptomic Atlas of Natural Killer (NK) Cells Reveals Intrinsic and Extrinsic Mediators of NK Cell Anti-Tumor Functions
Lozada, J. R., Ali, A. M., Day, A., Myers, J. A., Boytim, E., Bergom, H. E., Zorko, N. A., Felices, M., Miller, J. S., Hwang, J. H., et al. (2023) · Blood · doi:10.1182/blood-2023-187347
Integrated Single-Cell Profiling Reveals Dichotomous NK Cell Populations Associated with Immunosuppression in Solid Tumors
Lozada, J. R., Ali, A. M., Luo, C., Plagens, R. N., Zhang, B., Elliott, A., Boytim, E., Zorko, N. A., Heath, E. I., Patnaik, A., et al. (2026) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-25-1229 · Cited by 3 · see citing works
1010 A single-cell transcriptomic atlas of human NK cells to guide cancer immunotherapy
King, R., Amirabad, A., Bayegan, A. H., Theilhaber, J., Acuff, N. V., McGrath, S., Li, X., Rapaport, F., Pollard, J. R., & Jackson, D. (2022) · Regular and Young Investigator Award Abstracts · doi:10.1136/jitc-2022-sitc2022.1010
Tumor microenvironment-driven natural killer cell diversity: mechanisms and therapeutic opportunities
Duan, Y., Zhou, M., Guo, X., Cao, T., Lu, Y., & Zhao, X. (2026) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2025.0829
Mechanistic analysis of NK cells in pan-cancer tumor immunity
Song, J. (2024) · Theoretical and Natural Science · doi:10.54254/2753-8818/49/20241319

Authors: Tang, F., Li, J., Qi, L., Liu, D., Bo, Y., Qin, S., Miao, Y., Yu, K., Hou, W., Li, J., Peng, J., Tian, Z., Zhu, L., Peng, H., Wang, D., & Zhang, Z.
Affiliations: Peking University (CN)
Capital Medical University (CN)
Shenzhen Bay Laboratory (CN)
University of Science and Technology of China (CN)
Corresponding author: Zhu, Linnan
Peng, Hui
Wang, Dongfang
Zhang, Zemin
ORCID: Tang, Fei
Qi, Lu
Liu, Dongfang
Qin, Shishang
Miao, Yuhui
Yu, Kezhuo
Li, Jianan
Tian, Zhigang
Zhu, Linnan
Peng, Hui
Wang, Dongfang
Zhang, Zemin
Venue: Cell
Publisher: Elsevier BV
Published: 2023-09
Volume: 186
Issue: 19
Pages: 4235-4251.e20
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2023.07.034
OpenAlex: W4386034505
Cited by: 450
References: 91
Citations by year: 2026: 136 · 2025: 181 · 2024: 120 · 2023: 11 · 2022: 1 · 2012: 1
FWCI: 50.09
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Cell (publishedVersion, cc-by)
PubMed (publishedVersion)
Greater South Information System
Funders: National Natural Science Foundation of China (31991171, 592259205, 62203019, 81988101, 91959000, 92159305)
Peking University
Beijing Municipal Science and Technology Commission, Adminitrative Commission of Zhongguancun Science Park (Z221100007022002)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords: natural killer cells, pan-cancer, single-cell transcriptomics, NK cell subsets, cancer immunotherapy, dendritic cells, antitumor immunity
MeSH terms: Single-Cell Gene Expression Analysis, Dendritic Cells, Humans, Immunity, Innate, Immunotherapy, Killer Cells, Natural, Neoplasms, Myeloid Cells, Tumor Microenvironment

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

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