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

作者：Yifei Qin, Fei Huo, Zhuan Feng, Jialu Hou, Yaxin Ding, Quancheng Wang, Yu Gui, Ziwei Yang, Jiali Yang, Gang Zhou, Ling Li, Jian-Li Jiang, Ling‐Min Kong, Shijie Wang, Gang Nan, Ding‐Qiao Xu, Xiaohang Xie, Lijuan Wang, Qian He, Ruibin Yang, Peng Lin, Huijie Bian, Zhi‐Nan Chen, Jiao Wu · 发表于：Clinical and Molecular Hepatology · 年份：2025 · DOI：10.3350/cmh.2024.0948 · 被引用次数：28 · 研究领域：Cancer Immunotherapy and Biomarkers、Immune cells in cancer、Ferroptosis and cancer prognosis

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 a...