Hepatocellular carcinoma (HCC) is a highly fatal malignancy with limited therapeutic options and high recurrence rates. Recently, immunotherapeutic agents such as immune checkpoint inhibitors (ICIs) have emerged as a new paradigm shift in oncology. ICIs, such as programmed cell death protein 1 (PD-1) inhibitors, have provided a new source of hope for patients with advanced HCC. Yet, the eligibility criteria of HCC patients for ICIs are still a missing piece in the puzzle. Circular RNAs (circRNAs) have recently emerged as a new class of non-coding RNAs that play a fundamental role in cancer pathogenesis. Structurally, circRNAs are resistant to exonucleolytic degradation and have a longer half-life than their linear counterparts. Functionally, circRNAs possess the capability to influence various facets of the tumor microenvironment, especially at the HCC tumor–immune synapse. Notably, circRNAs have been observed to control the expression of immune checkpoint molecules within tumor cells, potentially impeding the therapeutic effectiveness of ICIs. Therefore, this renders them potential cancer-immune biomarkers for diagnosis, prognosis, and therapeutic regimen determinants. In this review, the authors shed light on the structure and functional roles of circRNAs and, most importantly, highlight the promising roles of circRNAs in HCC immunomodulation and their potential as promising biomarkers and immunotherapeutic regimen determinants.

According to data provided by World Health Organization, hepatocellular carcinoma (HCC) is the sixth most common cause of deaths due to cancer worldwide. Tremendous progress has been achieved over the last 10 years developing novel agents for HCC treatment, including small-molecule kinase inhibitors. Several small molecule inhibitors currently form the core of HCC treatment due to their versatility since they would be more easily absorbed and have higher oral bioavailability, thus easier to formulate and administer to patients. In addition, they can be altered structurally to have greater volumes of distribution, allowing them to block extravascular molecular targets and to accumulate in a high concentration in the tumor microenvironment. Moreover, they can be designed to have shortened half-lives to control for immune-related adverse events. Most importantly, they would spare patients, healthcare institutions, and society as a whole from the burden of high drug costs. The present review provides an overview of the pharmaceutical compounds that are licensed for HCC treatment and other emerging compounds that are still investigated in preclinical and clinical trials. These molecules are targeting different molecular targets and pathways that are proven to be involved in the pathogenesis of the disease.