Abstract
Psychological stress is increasingly linked to liver disease, but the underlying mechanisms remain unclear. Here we show that chronic stress disrupts a brain–liver circuit that impairs hepatic CD8+ T cell immunity and accelerates liver cancer progression. Using both oncogene-driven and carcinogen-driven liver cancer models in male mice, we find that psychological stress disrupts catecholamine/β2-adrenergic receptor (ADRB2) signalling, which suppresses the expression of quinolinate phosphoribosyl transferase (QPRT), an enzyme of the kynurenine pathway, in hepatocytes. QPRT loss diverts kynurenine metabolism away from nicotinamide adenine dinucleotide (NAD+) synthesis towards kynurenic acid (KA) accumulation. This shift results in mitochondrial impairment and reduced effector function of liver CD8+ T cells. We confirm that ADRB2/QPRT expression correlates with hepatic NAD+ and KA levels and with CD8+ T cell frequency and function in human liver tissues. Importantly, ADRB2/QPRT overexpression in hepatocytes, or nicotinamide administration, recovers CD8+ T cell function in stressed mice and reduces liver cancer progression. These findings identify a stress-responsive metabolic checkpoint in the liver that links the nervous system to immune surveillance and may be therapeutically targeted in liver cancers.
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Data availability
The RNA-seq data reported in this study have been deposited in the GEO database under accession no. GSE305657. All other data supporting the findings of this study are available within the article and Supplementary Information. Source data are provided with this paper.
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Acknowledgements
We thank the Translational Medicine Core Facility of Shandong University for consultation and instrument availability, all cancer patient volunteers who donated samples and the Laboratory Animal Center of Shandong University for the maintenance and management of laboratory animal feeding conditions, which supported this work. Extended Data Fig. 1a,c, Extended Data Fig. 5a, Fig. 5m, Extended Data Fig. 8d, Fig. 7i, Fig. 8f, Extended Data Fig. 10c and Supplementary Fig. 7 were prepared using BioRender software. This work was supported by grants from the National Key Research and Development Program (2022YFA1103402 to X.L.), the National Natural Science Foundation of China (82371754 to X.L., 82171805 to X.L., 81830017 to C.M. and 82321002 to C.M.), Taishan Scholarship (tstp20231212 to X.L.), Shandong University multidisciplinary research and innovation team of young scholars (2020QNQT001 to X.L.) and Cutting Edge Development Fund of Advanced Medical Research Institute (GYY2023QY01 to X.L.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
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X.L. and R.S. formulated the study concept. X.L. and R.S. designed the studies. R.S., D.J., W.Y., H.W., L.R., Z.F. and J.Z. performed the experiments. J.W. provided clinical samples and patient information. R.S. and X.L. analysed the results. X.L., C.M., L.G., C.L., Z.W., X.Y. and H.H. interpreted the results. R.S. and X.L. wrote and edited the paper.
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Extended data
Extended Data Fig. 1 Chronic stress accelerates liver metastasis of colorectal cancer and dampens CD8+ T cell anti-tumor immunity.
(A-B) MC-38 cells induced liver metastasis tumor model was established in control and CUMS mice. (A) Experimental design. (B) Survival curves of control and CUMS mice (n = 6 mice per group). (C-I) Control and CUMS mice bearing with MC-38 liver metastatic tumor were transferred with OT-1 CD8 + T cells (n = 6 mice per group). (C) Experimental design. (D) Representative liver images. (E) Gating strategy of CD45.1.2 + OT-1 CD8 + T cell subsets in liver tissues. FACS analysis of the number (F), apoptosis (G), exhaustion markers (H) and effector molecules (I) in liver OT-1 CD8+T cells from control and CUMS mice. Dots represent data from individual mice, and error bars indicate as the mean ± s.e.m. in one experiment. Statistical analyses were done by Log-Rank test (B) and two-tailed unpaired Student’s t test (D, F-I). Illustrations in A and C created in BioRender.com.
Extended Data Fig. 2 Chronic stress disturbs the homeostasis of CD8+ T cells in liver tissues.
(A) FACS analysis of CD45+ cell number in liver tissues from control and CUMS mice with oncogene-induced HCC (n = 5 mice per group). (B) Gating strategy of different immune cell subsets in liver tissues. (C) Flow cytometry analysis of the number of the indicated immune cell subsets in liver tissues from HCC bearing control and CUMS mice (n = 5 mice per group). (D) Depletion efficiency of CD8+ T cells using anti-CD8 antibody. (E) In vivo image of tumor burden in nude mice with oncogene-induced HCC (n = 6 mice per group). (F) FACS analysis of Ki-67 expression in liver CD8+T cells from control and CUMS mice with oncogene-induced HCC (n = 5 mice per group). (G-H) Percentage of TEM, TCM and Tnaive in liver CD8+ T cells from control and CUMS mice bearing cMyc/Akt-HCC (G, n = 5 mice per group) or DEN/CCl4-HCC (H, n = 8 mice per group). Dots represent data from individual mice, and error bars indicate as the mean ± s.e.m. in one experiment. Statistical analyses were done by two-tailed unpaired Student’s t test (A, C, E, F, G, H).
Extended Data Fig. 3 CUMS blunts the survival and functions of liver CD8+ T cells in an extrinsic manner.
(A-D) Purified liver CD8+T cells from control (labeled with CFSE) or CUMS (labeled with CTV) CD45.2 mice were transferred into CD45.1 recipient mice (n = 6 mice per group). Validation of the purity of mouse liver CD8+T cells for transfer experiment (A). Experimental scheme (B), FACS analysis of CD8+T cell percentage (C) and IFN-γ, TNF-α and GZMB expressions (D) were shown. (E-I) Purified liver CD8+T cells from donor mice (CD45.1) were transferred into control or CUMS mice (CD45.2) (n = 5 mice per group). Experimental scheme (E), the gating strategy of transferred liver CD8+T cell (CD45.1) in liver tissues of recipient mice (CD45.2) (F), FACS analysis of transferred CD8+T cell percentage (G), apoptosis (H) and IFN-γ, TNF, GZMB expressions (I) were shown. Dots represent data from individual mice, and error bars indicate as the mean ± s.e.m. in one experiment. Statistical analyses were done by two-tailed unpaired Student’s t test (C, D, G, H, I).
Extended Data Fig. 4 Adrb2 deficiency affects hepatic Kyn metabolism and CD8+ T cell homeostasis.
(A) Database analysis for mRNA expressions of adrenergic receptor in hepatocytes (Mouse Cell Atlas). (B-C) RT-qPCR (B) and Western blot (C) analysis of ADRB2 expression in hepatocytes and LMNCs from Adrb2f/f and Adrb2Δhep mice. (D) ELISA detection of NAD+, NAM and KA levels in hepatocytes from Adrb2f/f and Adrb2Δhep mice (n = 5 mice per group). (E-F) ELISA detection of NAD+ and NAM levels in liver CD8 + T cells from Adrb2f/f and Adrb2Δhep mice (n = 5 mice per group). (G-I) FACS analysis for the number (G), apoptosis (H), IFN-γ, TNF and GZMB expressions (I) in hepatic CD8+ T cells from Adrb2f/f and Adrb2Δhep mice (n = 5 mice per group). Dots represent data from individual mice, and error bars indicate as the mean ± s.e.m. in one experiment. Statistical analyses were done by two-tailed unpaired Student’s t test (B, D, E, F, G, H, I).
Extended Data Fig. 5 Combination of NAM and AHR inhibitors restores hepatocyte Adrb2 knockdown-induced CD8+ T cell disorder.
Primary hepatocytes transfected with siNC or siAdrb2, co-cultured with anti-CD3/CD28 activated CD8+T cells and treated with NAM (20 mM) and CH223191 (10 μM) for 24 h (n = 3 biologically independent samples). (A) Experimental schemes. (B-C) ELISA determination of NAD+ levels in hepatocytes (B) and co-cultured CD8+T cells (C). (D-F) FACS analysis of the apoptosis (D), killing activity against EL4 cells (E) and IFN-γ, TNF, GZMB expression (F) of co-cultured liver CD8+T cells. Dots represent data from different cell replicates, and error bars indicate as the mean ± s.e.m. in one experiment. Statistical analyses were done by two-tailed unpaired Student’s t test (B, C) or one-way ANOVA with Sidak’s multiple comparisons test (D, F) or Two-way ANOVA with Sidak’s multiple comparisons test (E). Illustration in A created in BioRender.com.
Extended Data Fig. 6 CUMS-induced catecholamine/ADRB2 axis dysregulation leads to imbalanced hepatocyte Kyn metabolism and CD8+T cells immunity.
(A-B) FACS plots and graphs for the apoptosis (A) and the expression of exhaustion markers (B) in liver CD8+ T cells from Adrb2Δhep and Adrb2f/f mice bearing oncogene-induced HCC with or without CUMS exposure (n = 6 mice per group). (C-D) FACS plots and graphs for the apoptosis (C) and the expression of exhaustion markers (D) in liver CD8+T cells from control and CUMS mice injected with AAV8-TBG-Adrb2 and bearing oncogene-induced HCC with or without CUMS exposure (n = 6 mice per group). (E-K) Control or CUMS mice subjected to DEN/CCl4-HCC model were intravenously injected with AAV8-TBG- Adrb2 at 6 weeks of age (n = 6 mice per group). (E) Experimental scheme, (F) Representative liver images and liver weight to bodyweight ratios from control and CUMS mice. (G) ELISA detection of NAD+, NAM and KA levels in hepatocytes. FACS analysis of the number (H), apoptosis (I), exhaustion markers (J) and effector molecules (K) in liver CD8+ T cells from control and CUMS mice. Dots represent data from individual mice, and error bars indicate as the mean ± s.e.m. in one experiment. Statistical analyses were done by one-way ANOVA with Sidak’s multiple comparisons test (A-D) or two-tailed Student’s unpaired t test (F-K).
Extended Data Fig. 7 Hepatocyte ADRB2/CREB signaling enhances QPRT expression.
(A-B) Primary mouse hepatocytes were transferred with siNC or siAdrb2 (n = 3 biologically independent samples). RT-qPCR analysis of Qprt expression (A), Western blot analysis of ADRB2, QPRT, p-CREB and CREB expression (B). (C) RT-qPCR analysis of Qprt expression in hepatocytes treated with colforsin (25 μM, 50 μM, or 100 μM) (n = 3 biologically independent samples). (D-E) Primary mouse hepatocytes were transfected with siNC or siAdrb2 and/or treated with colforsin (25 μM) (n = 3 biologically independent samples). RT-qPCR analysis of Qprt expression (D), Western blot analysis of QPRT, p-CREB and CREB expression (E). (F-G) RT-qPCR (F) and Western blot (G) analysis of QPRT and CREB expression in siNC or siCreb1 transfected hepatocytes. (H-J) RT-qPCR (H-I) and Western blot (J) analysis of QPRT, ADRB2 and CREB expression in siAdrb2 and/or siCreb1 transfected mouse hepatocytes. (K) The diagram showing the sequence of putative CREB binding motif and location of this motif in the promoter of mouse Qprt gene. (L) ChIP-qPCR analysis showing the recruitment of CREB to Qprt gene promoter regions in siNC or siAdrb2 transfected hepatocytes (n = 3 biologically independent samples). Dots represent data from individual mice or different cell replicates, and error bars indicate as the mean ± s.e.m. in one experiment. Statistical analyses were done by two-tailed unpaired Student’s t test (A, Fand L) or one-way ANOVA with Sidak’s multiple comparisons test (C, D, Hand I).
Extended Data Fig. 8 Qprt overexpression promotes hepatic CD8+ T cell homeostasis.
(A-C) Control and CUMS mice were injected with vector or AAV8-TBG-Qprt (n = 6 mice per group). Western blot and RT-qPCR analysis of Qprt expression in hepatocytes (A), FACS plots and graphs for the number (B) and the expression of exhaustion markers (C) in liver CD8+T cells. (D-I) Purified OT-1-CD8+T cells were co-cultured with Adrb2f/f and Adrb2Δhep hepatocytes infected with empty or Qprt-overexpressing lentivirus (n = 3 biologically independent samples). (D) Experimental schemes, (E) Western blot analysis of QPRT expression in hepatocytes. (F) ELISA determination of NAD+ and KA levels hepatocytes. (G) CD8+T cells killing activity against EL-4 cells. FACS analysis of apoptosis (H) and IFN-γ, TNF, GZMB expression (I) in CD8+T cells. Dots represent data from individual mice or different cell replicates, and error bars indicate as the mean ± s.e.m. in one experiment. Statistical analyses were done by one-way ANOVA with Sidak’s multiple comparisons test (A, B, C, F, H, I) or Two-way ANOVA with Sidak’s multiple comparisons test (G). Illustration in D created in BioRender.com.
Extended Data Fig. 9 NAM and KA inhibitors restore mitochondrial homeostasis in hepatic CD8+ T cells.
(A) FACS analysis of dysfunctional mitochondrial in liver CD8+T cells cocultured with Adrb2f/f and Adrb2Δhep hepatocytes infected with Lv-vector or Lv-Qprt (n = 3 biologically independent samples). (B-C) Liver CD8+T cells co-cultured with Adrb2f/f and Adrb2Δhep hepatocytes were treated with or without NAM (20 mM) and CH223191 (10 μM). (B) FACS analysis of dysfunctional mitochondrial in co-cultured CD8+T cells (n = 6 biologically independent samples). (C) Representative images for oxygen OCR and the basal respiration, maximum respiration, spare respiratory capacity and ATP production were analyzed in co-cultured CD8+T cells (n = 4 biologically independent samples). Dots represent data from different cell replicates, and error bars indicate as the mean ± s.e.m. in one experiment. Statistical analyses were done by one-way ANOVA with Sidak’s multiple comparisons test.
Extended Data Fig. 10 ADRB2 and QPRT expression correlates with Kyn metabolism and CD8+ T cell homeostasis in human liver organoids.
(A) The correlation between ADRB2 and QPRT expression in human hepatocytes was analyzed by TIMER web server (https://cistrome.shinyapps.io/timer/). (B) Kaplan-Meier analysis of overall survival in HCC patients in the cohort classified by ADRB2, QPRT expression and combined expression of ADRB2 and QPRT. Data were summarized from the TCGA-LIHC database. (C) Experimental procedures for HCC patients’ liver para-tumor tissues. Hepatocytes and mononuclear cells were isolated from normal liver tissues and used for measurement of ADRB2 expression, the NAD + /KA/NAM levels and CD8+T cell homeostasis. (D-F) Human normal liver tissues were collected and the correlation of hepatocyte ADRB2/QPRT expression with tryptophan metabolism was analyzed. (D) Correlation of ADRB2 and QPRT mRNA expression in normal human hepatocytes (n = 34). (E) Correlation analysis of ADRB2 mRNA level with liver NAD+, NAM, and KA levels (n = 34). (F) Correlation analysis of QPRT mRNA expression with liver NAD+, NAM, and KA levels (n = 34). (G-M) human liver organoid infected with Lv-ADRB2 or Lv-QPRT (n = 3 biologically independent samples). Western-blot analysis of ADRB2 or QPRT expression (G and H). ELISA analysis for the levels of NAD+ and KA in human liver organoid (I). FACS analysis of dysfunctional mitochondrial (J and K) and apoptosis (L and M) of cocultured CD8+ T cells. Dots represent data from different cell replicates, and error bars indicate as the mean ± s.e.m. in one experiment. Statistical analyses were done by two-tailed Pearson correlation analysis (D, E, F) two-tailed unpaired Student’s t test (I-M). Illustration in C created in BioRender.com.
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Sun, R., Jiao, D., Yuan, W. et al. Chronic stress drives liver cancer by impairing the hepatic kynurenine pathway and immune surveillance. Nat Metab 8, 196–214 (2026). https://doi.org/10.1038/s42255-025-01430-7
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DOI: https://doi.org/10.1038/s42255-025-01430-7
