Journal of hepatology · 2026
Tim-3 facilitates dendritic cell ferroptosis and impairs antitumor immunity in steatohepatitis-related HCC.
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Li Na, Song Xiaojia, Peng Xueqi, Li Mengzhen, Zhu Mengyao, Xiao Rong, Wang Liwen, Ling Leyan, Zhao Ying, Wang Tixiao, Zhou Zhiyuan, Wu Zhuanchang, Tang Hua, Gao Lifen, Liang Xiaohong, Li Chunyang, Ma Chunhong
Аннотация
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.
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.