Tim-3 facilitates dendritic cell ferroptosis and impairs anti-tumor immunity in steatohepatitis-related HCC.

[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] DC-CD8 T cell interaction in HCC tissues was 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. Therapeutic efficacy of Tim-3 blockade, alone or combined with anti-PD-1 or lenvatinib was evaluated in preclinical models.

[RESULTS] HFD reshapes the hepatic tumor immune microenvironment by inducing DC depletion and CD8 T cell dysfunction, facilitating liver tumor progression. In human steatohepatitic-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 synergizes 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 metabolic-associated steatohepatitic HCC.

[IMPACT AND IMPLICATIONS] Our findings identify Tim-3 as a crucial metabolic immune checkpoint that governs DC ferroptosis and DC-mediated antitumor immunity in metabolic liver cancer. Targeted blockade of Tim-3 in DCs holds great therapeutic potential for the treatment of steatohepatitic HCC, particularly for patients with MASLD-HCC who exhibit resistance to anti-PD-1 therapy.