PSMA for HCC: A New Frontier in Precision Medicine for Liver Cancer?

• Prostate-Specific Membrane Antigen (PSMA) is a novel target expressed in the tumor neovasculature of Hepatocellular Carcinoma (HCC), offering a new avenue for precision medicine. • PSMA-targeted PET imaging demonstrates high diagnostic sensitivity for HCC and identifies more lesions than conventional imaging or FDG-PET. • While preclinical studies show therapeutic promise for PSMA-radioligand therapy in HCC, its clinical efficacy is currently limited due to low tumor radiation doses and variable PSMA expression. • Future prospective trials are crucial to validate the role of PSMA-theranostics, particularly in combination with existing locoregional therapies, to improve HCC management. Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with limited therapeutic options and suboptimal outcomes, particularly in advanced stages. Conventional imaging modalities, including ultrasound, CT, and MRI, remain the cornerstone of diagnosis but show reduced sensitivity for small or atypical lesions. Molecular imaging has been investigated to overcome these limitations; however, ^18F-FDG PET demonstrates low sensitivity in well-differentiated HCC due to metabolic characteristics of the tumor. Prostate-specific membrane antigen (PSMA), initially studied in prostate cancer, has recently gained attention for its expression in the neovasculature of HCC. Immunohistochemical studies link PSMA expression to higher tumor grade, advanced stage, and poor prognosis. Clinical evidence indicates that PSMA-targeted PET provides superior sensitivity compared with FDG-PET and may enhance staging and treatment response assessment. Furthermore, PSMA targeted radioligand therapy (RLT) has shown efficacy in preclinical models, although early clinical experience suggests limited benefit, likely due to heterogeneous vascular expression. Major challenges include variable PSMA distribution, potential uptake in inflammatory liver processes, and the absence of prospective controlled trials. Nonetheless, PSMA-based imaging and therapy represent a promising frontier in precision medicine for HCC, warranting rigorous clinical validation and exploration in combination with established locoregional treatments.