Mechanistic Rationales guiding Combination Hepatocellular Carcinoma Therapies involving Immune Checkpoint Inhibitors.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers due to late symptom manifestation leading to delayed diagnosis which limits HCC patients from curative surgical treatment. There are only a few therapeutic options for advanced HCC patients. The emergence of immune checkpoint inhibitors (ICIs) brings HCC treatment to a new page in which Nivolumab, an anti-PD-1 monoclonal antibody, achieves 20% response rate. However, the large proportion of unresponsive patients drives the exploration on therapeutic strategies to improve ICIs' efficacy. Recent preclinical and clinical studies have suggested that ICIs when used in combinations or when used with other cancer therapies might elicit synergistic anti-tumor effects. However, the mechanistic rationales guiding different drug combinations to maximize the synergy remain largely ambiguous. In this review, we discuss different drug combinations used in HCC and the underlying mechanistic rationales, aiming to enhance the understanding on how these treatments can achieve synergy. This knowledge sets the foundation for the development of more effective and promising combination therapies for HCC.