CD36 promotes iron accumulation and dysfunction in CD8 T cells via the p38-CEBPB-TfR1 axis in earlystage hepatocellular carcinoma
Background/Aims The identification of factors that lead to CD8+ T cell dysfunction within the tumor microenvironment (TME) holds great promise for the development of innovative immunotherapies. However, the mechanisms underlying the exhausted phenotype of CD8+ T cells infiltrating early-stage hepato...
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| Format: | Article |
| Language: | English |
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Korean Association for the Study of the Liver
2025-07-01
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| Series: | Clinical and Molecular Hepatology |
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| Online Access: | http://e-cmh.org/upload/pdf/cmh-2024-0948.pdf |
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| author | Yifei Qin Fei Huo Zhuan Feng Jialu Hou Yaxin Ding Quancheng Wang Yu Gui Ziwei Yang Jiali Yang Gang Zhou Ling Li Jianli Jiang Lingmin Kong Shijie Wang Gang Nan Dingqiao Xu Xiaohang Xie Lijuan Wang Qian He Ruibin Yang Peng Lin Huijie Bian Zhi-Nan Chen Jiao Wu |
| author_facet | Yifei Qin Fei Huo Zhuan Feng Jialu Hou Yaxin Ding Quancheng Wang Yu Gui Ziwei Yang Jiali Yang Gang Zhou Ling Li Jianli Jiang Lingmin Kong Shijie Wang Gang Nan Dingqiao Xu Xiaohang Xie Lijuan Wang Qian He Ruibin Yang Peng Lin Huijie Bian Zhi-Nan Chen Jiao Wu |
| author_sort | Yifei Qin |
| collection | DOAJ |
| description | Background/Aims The identification of factors that lead to CD8+ T cell dysfunction within the tumor microenvironment (TME) holds great promise for the development of innovative immunotherapies. However, the mechanisms underlying the exhausted phenotype of CD8+ T cells infiltrating early-stage hepatocellular carcinoma (HCC) tumors remain unclear. Methods Single-cell RNA sequencing was performed using a murine HCC model. Flow cytometry and additional experimental approaches were employed to investigate the mechanisms of CD8+ T cell exhaustion. Results CD8+ T cells infiltrating early-stage HCC exhibited a functionally exhausted phenotype, which escalated with HCC progression. At early stages of HCC, the TME was characterized by significant iron accumulation. Moreover, tumor-infiltrating CD8+ T cells in murine HCC exhibited higher levels of intracellular ferrous iron compared to splenic CD8+ T. This excessive iron led to increased lipid peroxide levels and impaired the effector function of CD8+ T cells. Mechanistically, CD36 upregulated the iron uptake protein transferrin receptor 1 (TfR1) by mediating the activation of oxidized low-density lipoprotein (oxLDL)-p38-CEBPB axis. Depletion of CD36 in CD8+ T cells inhibited the upregulation of TfR1 and the increase of iron levels. Furthermore, constitutively activated nuclear factor erythroid 2-related factor 2 (NRF2) effectively suppressed lipid peroxidation, thereby preserving the effector functions of intratumoral CD8+ T cells and ultimately inhibiting tumor growth. Conclusions Our findings reveal a previously unidentified mechanism mediated by CD36 that regulates the progressive dysfunction of CD8+ T cells in early HCC TME and provide a potential novel therapeutic approach to restore T cell function. |
| format | Article |
| id | doaj-art-30bd5a3d7e44496182dfa87b39592abb |
| institution | DOAJ |
| issn | 2287-2728 2287-285X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Korean Association for the Study of the Liver |
| record_format | Article |
| series | Clinical and Molecular Hepatology |
| spelling | doaj-art-30bd5a3d7e44496182dfa87b39592abb2025-08-20T03:17:26ZengKorean Association for the Study of the LiverClinical and Molecular Hepatology2287-27282287-285X2025-07-0131396098010.3350/cmh.2024.09482202CD36 promotes iron accumulation and dysfunction in CD8 T cells via the p38-CEBPB-TfR1 axis in earlystage hepatocellular carcinomaYifei Qin0Fei Huo1Zhuan Feng2Jialu Hou3Yaxin Ding4Quancheng Wang5Yu Gui6Ziwei Yang7Jiali Yang8Gang Zhou9Ling Li10Jianli Jiang11Lingmin Kong12Shijie Wang13Gang Nan14Dingqiao Xu15Xiaohang Xie16Lijuan Wang17Qian He18Ruibin Yang19Peng Lin20Huijie Bian21Zhi-Nan Chen22Jiao Wu23 Institutes of Biomedicine and Department of Cell Biology, Jinan University, Guangzhou, China Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, 169 Changle West Road, 710032, China Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, 169 Changle West Road, 710032, China Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, 169 Changle West Road, 710032, China Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, 169 Changle West Road, 710032, China Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, 169 Changle West Road, 710032, China Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, 169 Changle West Road, 710032, China Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, 169 Changle West Road, 710032, China Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, 169 Changle West Road, 710032, China Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, 169 Changle West Road, 710032, China Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, 169 Changle West Road, 710032, China Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, 169 Changle West Road, 710032, China Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, 169 Changle West Road, 710032, China Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, 169 Changle West Road, 710032, China Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, 169 Changle West Road, 710032, China Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, 169 Changle West Road, 710032, China Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, 169 Changle West Road, 710032, China Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, 169 Changle West Road, 710032, China Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, 169 Changle West Road, 710032, China Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, 169 Changle West Road, 710032, China Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, 169 Changle West Road, 710032, China Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, 169 Changle West Road, 710032, China Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, 169 Changle West Road, 710032, China Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, 169 Changle West Road, 710032, ChinaBackground/Aims The identification of factors that lead to CD8+ T cell dysfunction within the tumor microenvironment (TME) holds great promise for the development of innovative immunotherapies. However, the mechanisms underlying the exhausted phenotype of CD8+ T cells infiltrating early-stage hepatocellular carcinoma (HCC) tumors remain unclear. Methods Single-cell RNA sequencing was performed using a murine HCC model. Flow cytometry and additional experimental approaches were employed to investigate the mechanisms of CD8+ T cell exhaustion. Results CD8+ T cells infiltrating early-stage HCC exhibited a functionally exhausted phenotype, which escalated with HCC progression. At early stages of HCC, the TME was characterized by significant iron accumulation. Moreover, tumor-infiltrating CD8+ T cells in murine HCC exhibited higher levels of intracellular ferrous iron compared to splenic CD8+ T. This excessive iron led to increased lipid peroxide levels and impaired the effector function of CD8+ T cells. Mechanistically, CD36 upregulated the iron uptake protein transferrin receptor 1 (TfR1) by mediating the activation of oxidized low-density lipoprotein (oxLDL)-p38-CEBPB axis. Depletion of CD36 in CD8+ T cells inhibited the upregulation of TfR1 and the increase of iron levels. Furthermore, constitutively activated nuclear factor erythroid 2-related factor 2 (NRF2) effectively suppressed lipid peroxidation, thereby preserving the effector functions of intratumoral CD8+ T cells and ultimately inhibiting tumor growth. Conclusions Our findings reveal a previously unidentified mechanism mediated by CD36 that regulates the progressive dysfunction of CD8+ T cells in early HCC TME and provide a potential novel therapeutic approach to restore T cell function.http://e-cmh.org/upload/pdf/cmh-2024-0948.pdfcd8 t cell dysfunctionlipid peroxidationiron accumulationhepatocellular carcinomacd36 |
| spellingShingle | Yifei Qin Fei Huo Zhuan Feng Jialu Hou Yaxin Ding Quancheng Wang Yu Gui Ziwei Yang Jiali Yang Gang Zhou Ling Li Jianli Jiang Lingmin Kong Shijie Wang Gang Nan Dingqiao Xu Xiaohang Xie Lijuan Wang Qian He Ruibin Yang Peng Lin Huijie Bian Zhi-Nan Chen Jiao Wu CD36 promotes iron accumulation and dysfunction in CD8 T cells via the p38-CEBPB-TfR1 axis in earlystage hepatocellular carcinoma Clinical and Molecular Hepatology cd8 t cell dysfunction lipid peroxidation iron accumulation hepatocellular carcinoma cd36 |
| title | CD36 promotes iron accumulation and dysfunction in CD8 T cells via the p38-CEBPB-TfR1 axis in earlystage hepatocellular carcinoma |
| title_full | CD36 promotes iron accumulation and dysfunction in CD8 T cells via the p38-CEBPB-TfR1 axis in earlystage hepatocellular carcinoma |
| title_fullStr | CD36 promotes iron accumulation and dysfunction in CD8 T cells via the p38-CEBPB-TfR1 axis in earlystage hepatocellular carcinoma |
| title_full_unstemmed | CD36 promotes iron accumulation and dysfunction in CD8 T cells via the p38-CEBPB-TfR1 axis in earlystage hepatocellular carcinoma |
| title_short | CD36 promotes iron accumulation and dysfunction in CD8 T cells via the p38-CEBPB-TfR1 axis in earlystage hepatocellular carcinoma |
| title_sort | cd36 promotes iron accumulation and dysfunction in cd8 t cells via the p38 cebpb tfr1 axis in earlystage hepatocellular carcinoma |
| topic | cd8 t cell dysfunction lipid peroxidation iron accumulation hepatocellular carcinoma cd36 |
| url | http://e-cmh.org/upload/pdf/cmh-2024-0948.pdf |
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