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Lactate dehydrogenase B facilitates disulfidptosis and exhaustion of tumour-infiltrating CD8+ T cells

Nature Cell Biology volume 27, pages 972–982 (2025)Cite this article

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Abstract

The aberrant accumulation of intracellular disulfides promotes cancer cell disulfidptosis; however, how disulfide stress influences tumour-infiltrating CD8+ T cell function remains unknown. Here we demonstrate that lactate dehydrogenase B (LDHB) facilitates intratumoural CD8+ T cell disulfidptosis and exhaustion, leading to impaired antitumour immunity. SLC7A11-mediated cystine uptake by CD8+ T cells induces disulfidptosis, which plays critical roles in the development of exhausted CD8+ T cells. LDHB restricts glucose-6-phosphate dehydrogenase (G6PD) activity in exhausted CD8+ T cells by interacting with G6PD, causing NADPH depletion and consequently triggering disulfidptosis. Accordingly, the loss of LDHB in T cells prevents disulfidptosis-dependent CD8+ T cell exhaustion and improves antitumour immunity. Mechanistically, STAT3 directs LDHB expression to limit G6PD activity and mediate disulfidptosis in exhausted CD8+ T cells. Our results highlight the distinct roles of disulfidptosis and ferroptosis in driving CD8+ T cell exhaustion and suggest a potential therapeutic strategy to target LDHB in cancer immunotherapy.

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Fig. 1: Intratumoural exhausted CD8+ T cells exhibit increased disulfidptosis.
Fig. 2: Disulfidptosis is involved in intratumoural exhausted CD8+ T cell development.
Fig. 3: G6PD inhibits intratumoural CD8+ T cell disulfidptosis and exhaustion.
Fig. 4: Disulfidptosis transcriptionally regulates exhausted CD8+ T cell differentiation.
Fig. 5: LDHB dampens CD8+ T cell antitumour responses.
Fig. 6: LDHB inhibits G6PD activity to promote CD8+ T cell disulfidptosis.
Fig. 7: STAT3 facilitates LDHB expression to inhibit G6PD in exhausted CD8+ T cells.

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Data availability

RNA-seq data that support the findings of this study have been deposited in the Genome Sequence Archive in National Genomics Data Center under accession codes CRA018798 and CRA022687. ATAC-seq data that support the findings of this study have been deposited in the Genome Sequence Archive in National Genomics Data Center under accession codes CRA018765 and CRA022688. The processed CRC public scRNA-seq datasets were collected from different databases, including Gene Expression Omnibus (GEO, https://www.ncbi.nlm.nih.gov/geo/, GSE178341, GSE164522 and GSE146771), GSA (https://ngdc.cncb.ac.cn/gsa-human/, HRA000979) and synapse (https://www.synapse.org/, syn26844071), which includes count matrices from five cohorts (SMC, CRC-SG1, CRC-SG2, KUL3 and KUL5). The processed LC public scRNA-seq dataset was downloaded from Gene Expression Omnibus (GEO, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE179994). The RCC public scRNA-seq dataset was downloaded from European Genome-phenome Archive (EGA, https://ega-archive.org/studies/EGAS00001002325). The pan-cancer scRNA-seq CD8+ T cells dataset with three cancer types (CRC, LC and RCC) was downloaded from an online data browser (http://cancer-pku.cn:3838/PanC_T). Source data are provided with this paper. All other data supporting the findings of this study are available from the corresponding authors on reasonable request.

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Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (grant no. 82225020, Q.Z.; grant no. 82430054, Q.Z.), the National Key Research and Development Program of China (grant no. 2020YFA0803603, Q.Z.; grant no. 2021YFA1301402, Q.Z.) and the Baoding Innovation Capability Enhancement Project (grant no. 2494F019, J.-H.L.).

Author information

Author notes

  1. These authors contributed equally: Jie Wan, Jian-Hong Shi, Min Shi, Haiyan Huang.

Authors and Affiliations

  1. Hongqiao International Institute of Medicine, Tongren Hospital & Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Jie Wan, Chenyue Guo, Rujuan Bao, Xiaoyan Yu, Qiaoqiao Han, Xian Du, Song Li, Youqiong Ye & Qiang Zou

  2. Central Laboratory, Hebei International Joint Research Center for Digital Twin Diagnosis and Treatment of Digestive Tract Tumors, Affiliated Hospital of Hebei University, Baoding, China

    Jian-Hong Shi

  3. Department of Gastroenterology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Min Shi

  4. Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Haiyan Huang

  5. Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China

    Zhen Zhang & Xia Li

  6. Department of Urology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Wenyan Li & Xingang Cui

  7. Department of Hepatobiliary Surgery, Baoding Key Laboratory of Precision Diagnosis and Treatment of Digestive Tract Tumors, Affiliated Hospital of Hebei University, Baoding, China

    Jing-Hua Li

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Contributions

J.W., J.-H.S., M.S. and H.H. designed and performed the experiments, prepared the figures and wrote the paper; Z.Z., W.L., C.G., R.B., X.Y., Q.H., X.D., S.L. and Y.Y. contributed to the performance of the experiments, X.C., X.L., J.-H.L. and Q.Z. supervised the work and wrote the paper.

Corresponding authors

Correspondence to Xingang Cui, Xia Li, Jing-Hua Li or Qiang Zou.

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Extended data

Extended Data Fig. 1 T cell development of Slc7a11fl/+Cd8-Cre and Slc7a11fl/+Cd4-Cre mice.

a, Flow cytometric analysis of the percentage of PD-1+Tim-3+ and IFN-γ+ CD8+ T cells in the exhaustion-induced condition in vitro in the presence of 5 mM disulfidptosis inhibitor (TCEP) at day 2, 4, 6 and 8 (n = 4). b, Flow cytometric analysis of the percentage of CD4+ and CD8+ T cells in the thymus, spleen and lymph node of Slc7a11+/+Cd8-Cre, Slc7a11fl/+Cd8-Cre and Slc7a11fl/flCd8-Cre mice (n = 3). c, Flow cytometric analysis of the percentage of CD4+ and CD8+ T cells in the thymus, spleen and lymph node of Slc7a11+/+Cd4-Cre and Slc7a11fl/+Cd4-Cre mice (n = 3). d, Flow cytometric analysis of the expressions of CD44 and CD62L in CD4+ and CD8+ T cells in the spleen of Slc7a11+/+Cd4-Cre and Slc7a11fl/+Cd4-Cre mice (n = 3). Data were presented as mean ± SEM. P values were calculated by two-tailed Student’s t test (a, c, d) or one-way ANOVA with Dunnett’s multiple comparison (b); ns, no statistically significance. In a-d, n indicates the number of biological replicates. For a-d, three independent experiments were performed.

Source data

Extended Data Fig. 2 T cell activity of Slc7a11fl/+Cd8-Cre and Slc7a11fl/+Cd4-Cre T cells.

a, The percentage of PD-1+Tim-3+ and IFN-γ+ cells of CD8+ T cells in exhaustion-induced condition in vitro at day 2, 4, 6 and 8 (n = 4). b, Actin cytoskeleton protein in exhausted Slc7a11+/+Cd8-Cre (labelled as 1), Slc7a11fl/+Cd8-Cre (labelled as 2) and Slc7a11fl/flCd8-Cre (labelled as 3) CD8+ T cells at day 2, 4, 6 and 8. c, FLNA in exhausted Slc7a11+/+Cd8-Cre (WT), Slc7a11fl/+Cd8-Cre (Her) and Slc7a11fl/flCd8-Cre (KO) CD8+ T cells. d, Actin cytoskeleton protein in exhausted Slc7a11+/+Cd4-Cre (WT) and Slc7a11fl/+Cd4-Cre (Her) CD8+ T cells. e, Intracellular cystine level (n = 4) and PD-1+Tim-3+ cell percentage (n = 3) of Slc7a11+/+Cd4-Cre (WT) and Slc7a11fl/+Cd4-Cre (Her) CD8+ T cells in exhaustion induced condition in vitro. f, The percentage of TNF-ɑ+ and IFN-γ+ in Slc7a11+/+Cd4-Cre and Slc7a11fl/+Cd4-Cre splenic CD4+ and CD8+ T cells stimulated with anti-CD3 (1 μg/ml) and anti-CD28 (1 μg/ml) for 48 hours (n = 4). g, Tumor size of Slc7a11+/+Cd4-Cre (WT) and Slc7a11fl/+Cd4-Cre (Her) mice injected s.c. with 5 × 105 MC38 colon cancer cells (n = 6). h, The percentage of tumor-infiltrating PD-1+Tim-3+, TNF-ɑ+, IFN-γ+ CD8+ T cells (n = 6) and IFN-γ+ (n = 6), Foxp3+ (n = 7), CXCR5+PD-1+ (n = 6) CD4+ T cells in tumors of Slc7a11+/+Cd4-Cre and Slc7a11fl/+Cd4-Cre mice injected with MC38 cells (day 16). i, Tumor growth of Slc7a11+/+Cd4-Cre (WT) and Slc7a11fl/+Cd4-Cre (Her) mice injected with MC38 cells. These mice were treated (i.p.) with 200 mg anti-CD4 (ɑ-CD4) or control antibody (IgG) every three days for five times (n = 6). Data were presented as mean ± SEM. P values were calculated by two-tailed Student’s t test (e, f, h), one-way ANOVA with Dunnett’s multiple comparison (a) or two-way ANOVA with Geisser-Greenhouse correction (g, i); ns, no statistically significance. In a, e-f, n indicates the number of biological replicates. In g-i, n indicates the number of mice. For a-i, three independent experiments were performed.

Source data

Extended Data Fig. 3 T cell development of G6pdfl/flCd4-Cre mice.

a, Flow cytometric analysis of the percentage of CD4+ and CD8+ T cells in the thymus, spleen and lymph node of G6pd+/+Cd4-Cre (WT) and G6pdfl/flCd4-Cre (KO) mice (n = 3). b, Flow cytometric analysis of the cell survival of G6pd+/+Cd4-Cre (WT) and G6pdfl/flCd4-Cre (KO) CD8+ T cells stimulated in vitro for 48 hours. c, Flow cytometric analysis of the percentage of PD-1+Tim-3+ cells of Slc7a11+/+Cd8-Cre (WT), Slc7a11fl/+Cd8-Cre (Her), TCEP-treated WT and Her CD8+ T cells in exhaustion-induced condition in vitro (n = 4). Data were presented as mean ± SEM. P values were calculated by two-tailed Student’s t test (a) or one-way ANOVA with Tukey’s multiple comparisons (c). ns, no statistically significance. In a,c, n indicates the number of biological replicates. For a-c, three independent experiments were performed.

Source data

Extended Data Fig. 4 T cell development of Ldhbfl/flCd4-Cre mice.

a, IP and IB analysis of the interaction of G6PD protein with LDHB protein in WT exhausted CD8+ T cells. b, Signature score of T cell exhaustion-associated gene set in CRC and RCC-infiltrating LDHBhigh (CRC, n = 27262; RCC n = 6529) and LDHBlow (CRC, n = 22246; RCC n = 5396) CD8+ T cells. The boxes in a show the median ±1 quartile, with the whiskers extending from the hinge to the smallest or largest value within 1.5× the interquartile range from the box boundaries. c, RT-qPCR analysis of the expression levels of CD8+ T cell exhaustion signature genes in RCC-infiltrating CD8+ T cells (n = 7). The lowest expression level of LDHB in RCC-infiltrating CD8+ T cells was normalized to 1. LDHBhigh group, higher than 1.2; LDHBlow group, less than 1.2. d, IB analysis of LDHB protein level in Ldhb+/+Cd4-Cre and Ldhbfl/flCd4-Cre CD8+ T cells. e, Flow cytometric analysis of the percentage of CD4+ and CD8+ T cells in the thymus, spleen and lymph node of Ldhb+/+Cd4-Cre and Ldhbfl/flCd4-Cre mice (n = 3). f, Flow cytometric analysis of the percentage of tumor-infiltrating CD4+ T cells in tumors of Ldhb+/+Cd4-Cre and Ldhbfl/flCd4-Cre mice injected s.c. with MC38 colon cancer cells (day 16; IFN-γ+, n = 5; Foxp3+, n = 6; CXCR5+PD-1+, n = 7). Data were presented as mean ± SEM. P values were calculated by two-sided Wilcoxon rank-sum test (b) or two-tailed Student’s t test (a,c,e,f). ns, no statistically significance. In b, n indicates the number of CD8+ T cells. In c, n indicates the number of human samples. In e, n indicates the number of biological replicates. In f, n indicates the number of mice. For a, d-f, three independent experiments were performed.

Source data

Extended Data Fig. 5 LDHB-G6PD axis in exhausted CD8+ T cells.

a, Native-PAGE analysis of the G6PD dimmer and G6PD monomer proteins in exhausted Ldhb+/+Cd4-Cre (WT) and Ldhbfl/flCd4-Cre (KO) CD8+ T cells. b, Heatmap of glycolysis-related metabolites in exhausted Ldhb+/+Cd4-Cre (WT) and Ldhbfl/flCd4-Cre (KO) CD8+ T cells (n = 3). c, IB analysis of LDHB protein levels in the cytosol and membrance of exhausted CD8+ T cells. Data were independently repeated 3 times (a,c). In b, n indicates the number of biological replicates. For a, c, three independent experiments were performed.

Source data

Extended Data Fig. 6 RNA-seq and ATAC-seq of exhausted Ldhbfl/flCd4-Cre CD8+ T cells.

a, Principal component analysis (PCA) of RNA-seq (upper panel) and ATAC-seq (lower panel) of exhausted Ldhb+/+Cd4-Cre and Ldhbfl/flCd4-Cre CD8+ T cells induced in vitro. b,c, Heatmap showing the differentially regulated gene expression (b) and peaks (c) among exhausted Ldhb+/+Cd4-Cre (WT) and Ldhbfl/flCd4-Cre (KO) CD8+ T cells (n = 3). d, qPCR analysis of the expression level of Ldhb in naïve (Tn) and exhausted (Tex) CD8+ T cells (n = 4). e, IB analysis of the protein level of LDHB in naïve (Tn) and exhausted (Tex) CD8+ T cells. Data were independently repeated 3 times (d,e). Data were presented as mean ± SEM and P values were calculated by two-tailed Student’s t test (d). In b-d, n indicates the number of biological replicates. For d, e, three independent experiments were performed.

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Wan, J., Shi, JH., Shi, M. et al. Lactate dehydrogenase B facilitates disulfidptosis and exhaustion of tumour-infiltrating CD8+ T cells. Nat Cell Biol 27, 972–982 (2025). https://doi.org/10.1038/s41556-025-01673-2

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