Immune checkpoints in hepatocellular carcinoma and the challenges of therapeutic resistance

Immune checkpoint inhibitors (ICIs) made a big change in the treatment of hepatocellular carcinoma (HCC), thereby bringing fresh hope in terms of treatment to patients with few options until that time. However, ICIs still encounter resistance mechanisms in a substantial number of patients, either in primary or secondary forms. This phenomenon of resistance occurs due to various reasons that comprise but are not restricted to epigenetic alterations, immunosuppressive tumor microenvironments, and activation of TGF-β and VEGF signaling pathways. In this study, we will discuss the mechanisms of ICI resistance in HCC and these emerging avenues of therapy as an approach to circumvent the resistance. The rationale and current status of ongoing trials to combine ICIs with anti-angiogenic agents, epigenetic modulating agents, and local therapies will be discussed. In a nutshell, we indicate an immediate need for reliable predictive biomarkers and personalized treatment approaches to improve clinical outcomes. Therefore, by managing challenges and knowledge gaps, this review presents a futurist outlook while charting a course for subsequent clinical trials designed to optimize immunotherapeutic results in HCC.