LAUSR

Simple Summary The use of anti-programmed cell-death protein (ligand)-1 (PD-[L]1) is now a standard of care for treating hepatocellular carcinoma (HCC). However, the treatment only benefits 10–20% of patients when used as a monotherapy. The unique environments of hepatitis and/or cirrhosis, which continuously interact with the hosts’ immune systems, make it difficult to find appropriate biomarkers to predict the response or lack of response of anti-PD-1/PD-L1 treatment in HCC. The current review aimed to present both clinical and translational biomarkers for anti-PD-1/PD-L1 treatment in HCC. Abstract The use of anti-programmed cell-death protein (ligand)-1 (PD-[L]1) is an important strategy for treating hepatocellular carcinoma (HCC). However, the treatment only benefits 10–20% of patients when used as a monotherapy. Therefore, the selection of patients for anti-PD-1/PD-L1 treatment is crucial for both patients and clinicians. This review aimed to explore the existing literature on tissue or circulating markers for the identification of responders or non-responders to anti-PD-1/PD-L1 in HCC. For the clinically available markers, both etiological factors (viral versus non-viral) and disease extent (intra-hepatic vs. extrahepatic) impact the responses to anti-PD-1/PD-L1, warranting further studies. Preliminary data suggested that inflammatory indices (e.g., neutrophil-lymphocyte ratio) may be associated with clinical outcomes of HCC during the anti-PD-1/PD-L1 treatment. Finally, although PD-L1 expression in tumor tissues is a predictive marker for multiple cancer types, its clinical application is less clear in HCC due to the lack of a clear-cut association with responders to anti-PD-1/PD-L1 treatment. Although all translational markers are not routinely measured in HCC, recent data suggest their potential roles in selecting patients for anti-PD-1/PD-L1 treatment. Such markers, including the immune classification of HCC, selected signaling pathways, tumor-infiltrating lymphocytes, and auto-antibodies, were discussed in this review.