## 1 Introduction  
Primary liver cancer, which in 75-85% of cases is represented by hepatocellular carcinoma (HCC), is the sixth most commonly diagnosed cancer and the third leading cause of cancer-related death globally [1]. The magnitude of this relevant health problem is predicted to rise in the near future, with a 55% projected increase in new cases of liver cancer per year between 2020 to 2040 [2]. Despite the widespread use of surgical and locoregional therapies worldwide, it is estimated that 50-60% of all patients with HCC will be ultimately treated with systemic therapies [3]. For several decades, no systemic drugs were available given the lack of efficacy of the evaluated molecules. A milestone in the systemic treatment of patients with advanced HCC was the approval of sorafenib in 2008, following the demonstration of its efficacy in two randomized clinical trials (RCTs) [4, 5]. With this achievement, the era of molecular-targeted therapies began. Tyrosine kinase inhibitors (TKIs) became the mainstay treatment of advanced HCC, holding the lead for more than a decade. These drugs as single agents demonstrated a clear survival benefit: a median overall survival (OS) of 11-14 months is achievable with first-line sorafenib and lenvatinib, while second-line regorafenib and cabozatinib grant an additional OS gain of 8-11 months [6]. Another breakthrough in the management of HCC was recently made,and currently we are witnessing the second revolution in the field of systemic therapies due to the demonstrated efficacy of immune-checkpoint inhibitors (ICIs). The positive results of the IMbrave150 trial, in which the combination of the anti-programmed death ligand 1 (PD-L1) atezolizumab and the anti-vascular endothelial growth factor A (VEGF-A) bevacizumab definitely demonstrated its superiority compared to sorafenib in patients with advanced stage HCC [7], are of the utmost importance. As a result of these findings, the more than 10-year TKIs-based treatment paradigm of advanced HCC has changed, and with this regimen a new benchmark for the median OS of approximately 19 months has been set [8]. The remarkable efficacy of immunotherapy in HCC was recently confirmed by the positive results of the HIMALAYA trial, in which the anti PD-L1 antibody durvalumab plus the anti-cytotoxic T lymphocyte antigen 4 (CTLA4) tremelimumab combination provided a statistically significant survival benefit compared to sorafenib in the first-line [9]. Moreover, this study also showed that durvalumab monotherapy is not inferior to sorafenib [9]. Considering the impressive survival benefit obtained with ICIIs-based regimens, the treatment of advanced HCC has entered the era of immunotherapy. Therefore, as expected, research is currently dominated by clinical trials investigating ICIIs combination therapies across all the stages of the disease, including adjuvant and neoadjuvant settings [3]. There is no doubt that ICIIs have revolutionized the treatment of advanced stage HCC and that represents a very important step forward. However, there is still a relevant proportion of patients receiving ICIs who do not benefit from the treatment. Indeed, approximately 40% of HCC patients do not achieve disease control with ICIs due to primary resistance, and a similar proportion will experience disease progression after an initial response (secondary resistance) [10]. The identification and development of predictive biomarkers capable of accurately identifying patients who will benefit from ICIs (responders) is of the utmost importance to better understand and overcome mechanisms of resistance and, hence, to enable a precision medicine approach in HCC immunotherapy. This represents an unmet medical need and a research challenge, as no validated biomarkers capable of predicting the outcome of ICIs-treated patients are currently available in clinical practice. Nevertheless, some studies have tried to define potential biomarkers for immune-based treatment strategies in HCC [3].