CD36 promotes iron accumulation and dysfunction in CD8 T cells via the p38-CEBPB-TfR1 axis in earlystage hepatocellular carcinoma

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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Main Authors: 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
Format: Article
Language:English
Published: Korean Association for the Study of the Liver 2025-07-01
Series:Clinical and Molecular Hepatology
Subjects:
cd8 t cell dysfunction
lipid peroxidation
iron accumulation
hepatocellular carcinoma
cd36
Online Access:http://e-cmh.org/upload/pdf/cmh-2024-0948.pdf
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Summary: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.
ISSN:2287-2728
2287-285X

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