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: 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: 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.