Using liver-directed therapies as backbone for combination-treatments in metastatic uveal melanoma

Metastatic uveal melanoma (mUM) remains a rare but highly lethal malignancy characterised by a strong predilection for liver metastases, which are the principal determinant of survival. Despite advances in systemic therapies, including immune checkpoint inhibitors and the T-cell−receptor bispecific molecule tebentafusp, durable disease control remains limited, particularly in liver-dominant disease. This has renewed interest in liver-directed therapies as both cytoreductive and immunomodulatory strategies. A broad range of locoregional approaches, including surgical resection, ablation, transarterial therapies, and hepatic perfusion techniques, have been investigated, with isolated hepatic perfusion and percutaneous hepatic perfusion (PHP) demonstrating the most robust clinical evidence. Emerging data suggest that liver-directed therapies may modulate the hepatic immune microenvironment, potentially enhancing antigen release and partially reversing local immunosuppression, although definitive mechanistic clinical evidence remains limited. This provides a biological rationale for combination strategies with immunotherapy. Early-phase and randomised trials, including the CHOPIN trial, indicate that combining PHP with a dual checkpoint blockade significantly improves clinical outcomes, albeit with increased grade 3-4 treatment-related adverse events (82% versus 41%). In the era of tebentafusp, liver-directed treatments are increasingly viewed as complementary modalities that may prolong systemic therapy benefit by controlling intrahepatic disease. Ongoing trials will define optimal sequencing and combinations. Collectively, these developments support a paradigm shift in which liver-directed therapies evolve into a central backbone of multimodal treatment strategies for selected patients with mUM.