Academic Journal
Tim-3 facilitates dendritic cell ferroptosis and impairs antitumor immunity in steatohepatitis-related HCC.
| Τίτλος: | Tim-3 facilitates dendritic cell ferroptosis and impairs antitumor immunity in steatohepatitis-related HCC. |
|---|---|
| Συγγραφείς: | Li N; Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Shandong University Cancer Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China., Song X; Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Shandong University Cancer Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China., Peng X; Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Shandong University Cancer Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China., Li M; Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Shandong University Cancer Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Department of Clinical Laboratory, Qilu Hospital, Shandong University (Qingdao), Qingdao, China., Zhu M; Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Shandong University Cancer Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China., Xiao R; Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Shandong University Cancer Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Department of Radiation Oncology, Shandong Provincial Key Laboratory of Precision Oncology, Shandong University Cancer Center, Jinan, Shandong 250012, China., Wang L; Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Shandong University Cancer Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China., Ling L; Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Shandong University Cancer Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China., Zhao Y; Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Shandong University Cancer Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China., Wang T; Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Shandong University Cancer Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China., Zhou Z; Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Shandong University Cancer Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China., Wu Z; Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Shandong University Cancer Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China., Tang H; Institute of Infection and Immunity, Medical Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250012, China., Gao L; Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Shandong University Cancer Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China., Liang X; Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Shandong University Cancer Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China., Li C; Shandong University Cancer Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China. Electronic address: lichunyang@sdu.edu.cn., Ma C; Shandong University Cancer Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong 250012, China. Electronic address: machunhong@sdu.edu.cn. |
| Πηγή: | Journal of hepatology [J Hepatol] 2026 Aug; Vol. 85 (2), pp. 331-344. Date of Electronic Publication: 2026 Apr 24. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Country of Publication: Netherlands NLM ID: 8503886 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1600-0641 (Electronic) Linking ISSN: 01688278 NLM ISO Abbreviation: J Hepatol Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2001- : Amsterdam : Elsevier Original Publication: Copehnagen : Munksgaard International Publishers, [c1984- |
| Ιατρικοί όροι (MeSH): | Hepatitis A Virus Cellular Receptor 2*/metabolism , Hepatitis A Virus Cellular Receptor 2*/antagonists & inhibitors , Hepatitis A Virus Cellular Receptor 2*/genetics , Ferroptosis*/immunology , Dendritic Cells*/immunology , Dendritic Cells*/metabolism , Carcinoma, Hepatocellular*/immunology , Carcinoma, Hepatocellular*/etiology , Carcinoma, Hepatocellular*/pathology , Liver Neoplasms*/immunology , Liver Neoplasms*/etiology , Liver Neoplasms*/pathology , Fatty Liver*/complications , Fatty Liver*/immunology , Non-alcoholic Fatty Liver Disease*/complications , Non-alcoholic Fatty Liver Disease*/immunology, CD8-Positive T-Lymphocytes/immunology ; Tumor Microenvironment/immunology ; Diet, High-Fat/adverse effects ; Animals ; Mice ; Humans ; Male ; Mice, Inbred C57BL ; Disease Models, Animal |
| Περίληψη: | Background & Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of hepatocellular carcinoma (HCC) and confers resistance to immunotherapy. However, the underlying mechanisms remain unclear. We aimed to elucidate how the lipid-rich microenvironment of MASLD-HCC drives immune suppression and to identify actionable targets. Methods: Dendritic cell (DC)-CD8+ T cell interactions in HCC tissues were analyzed by multiplexed immunofluorescence staining. Mechanistic studies employed high-fat diet (HFD)-induced MASLD-HCC mouse models, genetic or pharmacological inhibition of Tim-3, and DC depletion or adoptive transfer. Lipid peroxidation, ferroptosis, and immune interactions were assessed using flow cytometry, transcriptomics, and functional assays. The therapeutic efficacy of Tim-3 blockade, alone or combined with anti-PD-1 therapy or lenvatinib, was evaluated in preclinical models. Results: HFD reshaped the hepatic tumor immune microenvironment by inducing DC depletion and CD8+ T cell dysfunction, facilitating liver tumor progression. In human steatohepatitis-related HCC, DC infiltration and DC-CD8+ T cell interactions were markedly impaired, and high DC-specific Tim-3 expression correlated with poor prognosis. Mechanistically, the lipid-rich microenvironment induced DC depletion via Tim-3-dependent lipid peroxidation and ferroptosis. Genetic or pharmacological inhibition of Tim-3 in DCs attenuated lipid peroxidation, restored DC survival and CD8+ T cell activation, and suppressed tumor growth. Moreover, Tim-3 blockade synergized effectively with both anti-PD-1 and lenvatinib to achieve sustained tumor control. Conclusion: Our findings establish Tim-3 as a pivotal regulator of DC ferroptosis in metabolic liver cancer. Combining Tim-3 blockade with standard therapies represents a promising strategy to restore immune surveillance in MASLD-HCC. Impact and Implications: Our findings identify Tim-3 as a crucial metabolic immune checkpoint that governs dendritic cell ferroptosis and dendritic cell-mediated antitumor immunity in metabolic liver cancer. Targeted blockade of Tim-3 in dendritic cells holds great therapeutic potential for the treatment of steatohepatitis-related hepatocellular carcinoma, particularly for patients with metabolic dysfunction-associated steatotic liver disease-related hepatocellular carcinoma who exhibit resistance to anti-PD-1 therapy. (Copyright © 2026 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.) |
| Competing Interests: | Conflicts of interest The authors declare no competing financial interests. Please refer to the accompanying ICMJE disclosure forms for further details. |
| Contributed Indexing: | Keywords: Hepatocellular carcinoma; Tim-3; dendritic cells; ferroptosis; metabolic dysfunction-associated steatotic liver disease |
| Substance Nomenclature: | 0 (Hepatitis A Virus Cellular Receptor 2) 0 (Havcr2 protein, mouse) 0 (HAVCR2 protein, human) |
| Entry Date(s): | Date Created: 20260426 Date Completed: 20260716 Latest Revision: 20260716 |
| Update Code: | 20260717 |
| DOI: | 10.1016/j.jhep.2026.04.010 |
| PMID: | 42035954 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1600-0641 |
|---|---|
| DOI: | 10.1016/j.jhep.2026.04.010 |