Tim-3 blockade controls tumour growth in metabolic liver cancer

In patients with steatohepatitis-related hepatocellular carcinoma (HCC), Tim-3 plays a key role in regulating dendritic cell (DC) ferroptosis, with its expression predicting poor prognosis, suggests a study.

A team of investigators analysed DC-CD8+ T-cell interactions in HCC tissues using multiplexed immunofluorescence staining. In mechanistic studies, high-fat diet-induced metabolic dysfunction-associated steatotic liver disease (MASLD)-HCC mouse models were employed, as well as genetic or pharmacological inhibitor of Tim-3, and DC depletion or adoptive transfer.

Flow cytometry, transcriptomics, and functional assays were used to assess lipid peroxidation, ferroptosis, and immune interactions. Finally, preclinical models were used to examine the therapeutic efficacy of Tim-3 blockade, alone or combined with anti-PD-1 therapy or lenvatinib.

The high-fat diet reshaped the hepatic tumour immune microenvironment through DC depletion and CD8+ T-cell dysfunction, which facilitated liver tumour progression. DC infiltration and DC-CD8+ T-cell interactions were notably impaired in human steatohepatitis-related HCC, and high DC-specific Tim-3 expression was significantly associated with poor prognosis.

Mechanistically, the lipid-rich microenvironment enabled DC depletion via Tim-3-dependent lipid peroxidation and ferroptosis.

Notably, genetic or pharmacological inhibition of Tim-3 in DCs mitigated lipid peroxidation, restored DC survival and CD8+ T-cell activation, and suppressed tumour progression. Tim-3 blockade also effectively synergized with both anti-PD-1 and lenvatinib, resulting in sustained tumour control.

“Our findings establish Tim-3 as a pivotal regulator of DC ferroptosis in metabolic liver cancer,” the  investigators said. “Combining Tim-3 blockade with standard therapies represents a promising strategy to restore immune surveillance in MASLD-HCC.”