Related Experiment Video For Hepatocellular carcinoma
Updated: May 21, 2026
An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
Tim-3 facilitates dendritic cell ferroptosis and impairs antitumor immunity in steatohepatitis-related HCC
Na Li1, Xiaojia Song1, Xueqi Peng1
1Key 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.
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.
