Current Immunotherapy Strategies and Emerging Biomarkers for the Treatment of Hepatocellular Carcinoma

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.

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.

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.

We review current research and its integration into clinical practice, advancing HCC therapy toward personalized, patient-centered care.