Abstract
BACKGROUND/OBJECTIVES: Hepatocellular carcinoma (HCC), the predominant form of liver cancer, ranks as the third leading cause of cancer-related deaths worldwide. With the shift from viral hepatitis to metabolically dysfunction-associated steatosis liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) as primary etiologies, we aimed to review ongoing clinical trials in adult HCC patients to highlight emerging treatments, particularly for nonviral HCC cases. METHODS: We searched ClinicalTrial.gov (last March 2025) for interventional trials. We included ongoing (recruiting/active/not recruiting), phase I-IV, adults (>18 years old), and HCC-focused only clinical trials. We excluded observational and interventional (biological, genetic, device, or procedure) clinical trials. RESULTS: This review highlights recent advances in HCC treatment, with a focus on the transformative role of immunotherapy. Evidence suggests that nonviral HCC, as well as HCC with MASLD/MASH background livers, may have reduced sensitivity to immunotherapy. Thus, there is a critical need for molecular insights to improve patient stratification. Moreover, we examine how new diagnostic tools, including liquid biopsies, influence treatment decisions and aid in monitoring responses. Limitations limited MASLD/MASH-specific trial data. CONCLUSIONS: We review current research and its integration into clinical practice, advancing HCC therapy toward personalized, patient-centered care.