Abstract
Natural killer (NK) cells are essential for controlling tumor metastasis, but their protective capacity diminishes when entering an exhaustion state. The mechanisms underlying NK cell exhaustion are incompletely understood. Here, we show that the susceptibility of NK cells to exhaustion is predetermined early during their development and is governed by the transcription factor IRF4. Notably, IRF4 is highly expressed in CD27−CD24+ NK precursors but is nearly absent in immature and mature NK cells. Deletion of IRF4 redirects NK cell development, enabling NK precursors to generate more mature NK cells that resist exhaustion, thereby decreasing melanoma lung metastasis. This resistance to exhaustion is evident by increased effector molecule production and decreased expression of inhibitory receptors such as TIGIT and Pik3ip1. Deleting Pik3ip1 also enhances NK cell ability to counteract melanoma lung metastasis. These findings enhance our understanding of NK cell exhaustion and have implications for preventing cancer metastasis using NK cells.
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Data availability
RNA-seq, scRNA-seq and ATAC-seq data have been deposited in the Gene Expression Omnibus under accession codes GSE249188, GSE249230 and GSE283690. Raw Illumina sequencing reads of RNA-seq, scRNA-seq and ATAC-seq datasets were aligned to reference mouse genome mm10 (Ensembl 93), http://jul2018.archive.ensembl.org/Mus_musculus/Info/Index. All other data supporting the findings of this study are available within the article and Supplementary Information. Source data are provided with this paper.
Code availability
ScRNA-seq and ATAC-seq data analyses were conducted using publicly available codes and open-source software packages. No new algorithms were developed for this study.
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Acknowledgements
We thank E. Vivier (Aix Marseille University) for the Ncr1Cre mouse strain and L. L. Lanier (University of California San Francisco) for the RMA-S cell line. We would like to thank the Single Cell Genomics Core at Baylor College of Medicine, the Biostatistics and Bioinformatics (BBI) shared resources at Houston Methodist Neal Cancer Center and the Houston Methodist Flow Cytometry Core Facility for their excellent services. This work was supported by internal fund from Houston Methodist Research Institute (to W.C.).
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X.Z., J.W., X.X. and W.C. designed the study. X.Z., X.C.L. and W.C. wrote the manuscript. X.Z. performed core experimental work and data analysis. Z.Y. performed computational analyses. J.W., X.X., D.Z., G.W., J.F., P.L., L.J.M., X.C.L. and W.C. performed supporting experimental work and data analysis.
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Nature Immunology thanks Dagmar Gotthardt and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Nick Bernard, in collaboration with the Nature Immunology team. Peer reviewer reports are available.
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Extended data
Extended Data Fig. 1 IRF4 deletion in T cells, dendritic cells, or macrophages does not reduce melanoma metastasis.
(a) Representative image of lung metastasis in Irf4fl/fl and Irf4fl/flCd4-Cre mice 20 days post B16-F10 cell intravenous injection, and a graph showing percentage survival rates for the injected mice. n = 6 mice per group; ns, not significant. (b) Representative lung metastasis image (day 20 post B16-F10 cell injection) in Irf4fl/fl and Irf4fl/flLysM-Cre mice, and percentage survival rates. n = 7 mice per group; ns, not significant. (c) Percentage survival rates of Irf4fl/flCd11c-Cre and Irf4fl/fl mice post B16-F10 cell intravenous injection. n = 5 mice per group; ns, not significant. (d) Percentages of remaining CD3‒NK1.1+ cells within splenocytes of WT and Irf4–/– mice three days post anti-NK1.1 mAb (clone PK136) treatment. Results are representative of two or three independent experiments. Data were analyzed by a log-rank test.
Extended Data Fig. 2 Irf4‒/‒ NK cells exhibit a more mature phenotype.
(a) Representative flow cytometry plots of CD3‒NK1.1+ cells and bar graphs showing NK cell numbers in the liver and blood (per ml) of naïve WT and Irf4−/− mice. For the liver, n = 6 mice per group, **P = 0.0022; for the blood, n = 5 mice per group, ***P = 0.0001. (b) Representative flow cytometry plots show CD27 and CD11b expression in NK cells. The bar graph shows the percentage of CD27‒CD11b+ cells among total NK cells in the indicated tissues of naïve WT and Irf4−/− mice. n = 6 mice per group; from left to right: ****P < 0.0001, ***P = 0.0009, ***P = 0.0010, * P = 0.0128. (c) Sorted NK cells from naïve WT and Irf4−/− mice were labeled with CTV and stimulated in vitro with IL-12 (10 ng/ml), IL-18 (50 ng/ml), and IL-15 (50 ng/ml) for 3 days to assess proliferation. (d) Sorted NK cells from naïve WT and Irf4−/− mice were stimulated in vitro with IL-12, IL-18, and IL-15 for 3 days, followed by apoptosis assessment. n = 5 biologically independent samples per group; ****P < 0.0001. Data are presented as mean ± SD (a,b,d). Results are representative of two or three independent experiments. Data were analyzed by a two-tailed unpaired Student’s t-test.
Extended Data Fig. 3 Irf4–/– BM cell reconstitution does not enhance the generation of other immune cells.
(a) Flow cytometry analysis confirming that WT and Irf4–/– BM cells were mixed at a 1:1 ratio prior to transfer into lethally irradiated Rag1–/– mice. (b) Flow cytometry analysis of the percentage of NKP cells in the bone marrow of WT and Irf4–/– mice. n = 3 mice per group; ns, not significant. (c and d) Lethally irradiated Rag1−/− mice were reconstituted with a 1:1 mixture of CD45.1+ WT and CD45.2+ Irf4–/– BM cells. Flow cytometry was performed 6 weeks post transfer to assess the percentage of live cells (c) and CD3+NK1.1– T cells (d) derived from transferred WT or Irf4–/– BM cells. n = 3 mice; for c: ***P = 0.0003, ns, not significant; for d: **P = 0.0052, ns, not significant. Results are representative of two or three independent experiments. Data are presented as mean ± SD (b,c,d). Data were analyzed by a two-tailed unpaired Student’s t-test.
Extended Data Fig. 4 IRF4 expression in NKP and NK cells during melanoma metastasis.
(a and b) Irf4GFP reporter mice were intravenously injected with B16-F10 cells. Shown are the percentages of IRF4.GFP+ cells within NK cells in spleen and lung (a) and the percentages of IRF4.GFP+CD27‒ cells within BM NKP cells (b) at different time points post B16-F10 injection. n = 3 mice per time point. (c and d) Rag2−/−γc−/− mice were transferred with a 1:1 mixture of WT and Irf4−/− NKP cells. (c) Gating strategy used to sort BM NKP cells for transfer. (d) Percentages of NK cells derived from the transferred WT or Irf4−/− NKP cells at 6 weeks post-transfer. n = 4 mice; **P = 0.0021. Data are presented as mean ± SD (a,b,d). Data were analyzed by a two-tailed unpaired Student’s t-test (d).
Extended Data Fig. 5 Identification of IRF4-expressing CD24+CD27– NKP cells.
(a and b) scRNA-seq analysis of a total of 20,836 cells, including 12,740 WT NKP and 8,096 Irf4−/− NKP cells. UMAP plots (a) illustrating the normalized expression of Irf4 and Cd24a in NKP cells. Bubble plots (b) illustrating the normalized expression of Irf4 and Cd24a across identified NKP cell clusters (matching cluster IDs in Fig. 3a). The color intensity corresponds to the average expression level within the cluster. The size of each bubble indicates the percentage of cells expressing the gene within the cluster. (c–e) CD24‒CD27+ NKP cells from WT CD45.1+ BM and CD24+CD27‒ NKP cells from WT CD45.2+ BM were adoptively co-transferred into Rag2−/−γc−/− mice in a 1:1 ratio, followed by flow cytometry analysis six weeks later. Shown are percentages of CD45.1+ and CD45.2+ cells among CD3–NK1.1+ splenocytes (c, n = 3 mice, **P = 0.0036), expression of CD27 versus CD11b among CD3–NK1.1+ splenocytes derived from the transferred NKP cells (d), and expression of CD27 in CD3–NK1.1– splenocytes derived from the transferred NKP cells (e). (f) CD27–CD24med NKP cells from WT CD45.1+ BM and CD27–CD24high NKP cells from WT CD45.2+ BM were adoptively co-transferred into Rag2−/−γc−/− mice in a 1:1 ratio. The percentages of splenic CD3‒NK1.1+ NK cells derived from these transferred NKP cells were assessed two weeks post-transfer (n = 3 mice; ****P < 0.0001). Data are presented as mean ± SD (c,f). Data were analyzed by a two-tailed unpaired Student’s t-test (c,f).
Extended Data Fig. 6 Evaluation of NK cells from WT and Irf4‒/‒ mice.
(a,b) Splenic NK cells from naïve WT and Irf4‒/‒ mice were stimulated with IL-12, IL-15, and IL-18. Shown are the percentages of IFN-γ+ and perforin+ cells (a), as well as granzyme B+ cells (b), within WT and Irf4‒/‒ NK cells. For IFN-γ, n = 5 mice per group; for perforin, n = 4 mice per group; for granzyme B, n = 3 mice per group; ns, not significant. (c) Splenic NK cells from naïve WT and Irf4‒/‒ mice were cocultured with RMA/S-GFP target cells at the indicated ratios. Percentage killing of target cells were illustrated. n = 3 biologically independent samples per group. (d) Percentages of granzyme B+ cells within lung NK cells, comparing WT versus Irf4–/– mice 20 days post B16-F10 cell intravenous injection. n = 3 mice per group; **P = 0.0038. (e) Expression of TIGIT in NK cells from the spleens of naïve WT and Irf4−/− mice. n = 4 mice per group; ns, not significant. (f) NK cells sorted from the spleens of naïve WT and Irf4−/− mice were stimulated in vitro with plate-bound anti-NK1.1 (PK136) antibody (20 µg/ml), IL-2 (10 ng/ml), and IL-15 (5 ng/ml) for 3 days, followed by assessment of TIGIT expression. n = 6 biologically independent samples per group; ****P < 0.0001. Data are presented as mean ± SD. Data were analyzed by a two-tailed unpaired Student’s t-test.
Extended Data Fig. 7 Deleting IRF4 in Ncr1-expressing NK cells does not prolong survival in the melanoma metastasis model.
(a) Irf4fl/fl mice from Jackson Laboratory contain an eGFP gene positioned in the opposite orientation upstream of the Irf4 promoter. Upon Cre-mediated Irf4 deletion, eGFP is expressed, although at low levels in some cells. Shown is GFP expression in NK cells from the spleens of naïve Irf4fl/fl and Irf4fl/flNcr1Cre+/‒ mice. (b) Expression of Nkp46 in NK cells from the spleens of naïve Irf4fl/fl and Irf4fl/flNcr1Cre+/‒ mice. (c) Percentages of Nkp46+ cells among CD3‒NK1.1+ splenocytes in naïve Irf4fl/fl and Irf4fl/flNcr1Cre+/‒ mice. n = 3 mice per group; ns, not significant. (d) Percentage survival rates of Irf4fl/fl, Irf4w/wNcr1Cre+/‒, and Irf4fl/flNcr1Cre+/‒ mice following intravenous injection of B16-F10 cells. n = 5 mice per group; ns, not significant. Data are presented as mean ± SD (c). Data were analyzed by a two-tailed unpaired Student’s t-test (c) and a log-rank test (d).
Extended Data Fig. 8 Irf4 deficiency in NKP cells renders mature NK cells less prone to exhaustion.
(a and b) Rag2−/−γc−/− mice were transferred with a 1:1 mixture of CD45.1+ WT NKP and CD45.2+ Irf4−/− NKP cells. Two weeks later, the mice were intravenously injected with B16-F10 cells. Splenic NK cells derived from the transferred NKP cells were analyzed 14 days after B16-F10 injection. Shown are the percentages of WT and Irf4–/– NK cells among total splenic NK cells (a) and the percentages of TIGIT+ cells within WT and Irf4–/– NK cells (b). For a: n = 3 mice, ***P = 0.0002; for b: n = 4 mice, ***P = 0.0008. (c) Lethally irradiated Rag1−/− mice were reconstituted with a 1:1 mixture of CD45.1+ WT BM and CD45.2+ Irf4–/– BM cells. Six weeks later, the mice were injected with B16-F10 cells. NK cells derived from the transferred BM NKP cells were analyzed 25 days after B16-F10 injection. The top flow plots show the percentages of WT and Irf4–/– NK cells, and the bottom flow plots show TIGIT expression in WT and Irf4–/– NK cells in the indicated tissues. The bar graph shows the percentages of TIGIT+ cells within WT and Irf4–/– NK cells. n = 6 mice; from left to right: ****P < 0.0001 ****P < 0.0001, *P = 0.0162, ****P < 0.0001, ****P < 0.0001. Data are presented as mean ± SD. Data were analyzed by a two-tailed unpaired Student’s t-test.
Extended Data Fig. 9 Chromatin accessibility at indicated loci in NK cells.
ATAC-seq was performed on NK cells sorted from naïve WT, Irf4–/–, Irf4fl/fl, and Irf4fl/flNcr1Cre+/‒ mice (related to Fig. 6). Genome tracks show chromatin accessibility at the Prf1, Ifng, Tigit and Gzmb loci across the indicated NK cell groups.
Extended Data Fig. 10 Pik3ip1 deficiency reduces NK cell exhaustion during melanoma metastasis.
(a) Percentages of NK cells in the spleen of naïve WT and Pik3ip1‒/‒ mice. n = 5 mice per group; ns, not significant. (b) Percentages of TIGIT+ cells within spleen and lung NK cells, comparing WT vs. Pik3ip1‒/‒ mice 20 days post B16-F10 cell injection. n = 3 mice per group; *P = 0.0169, **P = 0.0050. (c) Percentages of IFN-γ+ and perforin+ cells within lung NK cells, comparing WT vs. Pik3ip1‒/‒ mice 20 days post B16-F10 injection. n = 3 mice per group; **P = 0.0023, *P = 0.0155. Data are presented as mean ± SD. Results are representative of two or three independent experiments. Data were analyzed by a two-tailed unpaired Student’s t-test.
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Zhang, X., Yin, Z., Wu, J. et al. IRF4 expression by NK precursors predetermines exhaustion of NK cells during tumor metastasis. Nat Immunol 26, 1062–1073 (2025). https://doi.org/10.1038/s41590-025-02176-w
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DOI: https://doi.org/10.1038/s41590-025-02176-w
