**1. Introduction**

Hepatocellular carcinoma (HCC) is the prevalent primary liver carcinoma and the largest cause of cancer-associated deaths across the globe. HCC accounts for ~90% of cases. Hepatitis B and C virus infections, liver flukes in endemic areas, excessive intake of alcohol, cigarettes, elevated level of body fat, and aflatoxins are all significant risk factors for developing HCC. The tumor burden, liver functioning, comorbidities, and health condition of a patient influence treatment options for HCC. HCC treatments have changed dramatically over the past four decades. Surgical or organ transplantation is the first-line treatment for tumors less than 5 cm in diameter. However, the treatment of large HCCs (those greater than 10 cm) is disputed, with considerable heterogeneity in various treatment regimens in different locations [1]. Additionally, radiofrequency ablation (RFA) and transarterial chemoembolization (TACE) are the local modalities utilized for early and intermediate-stage HCC, accordingly [2, 3]. Systemic treatments for advanced-stage HCC were found controversial prior to 2008

because of their ineffectiveness and poor patient tolerability. Moreover, systemic treatments for liver cancers have made little progress in the last decade.

Immuno-oncology has revolutionized cancer treatment, particularly liver cancer, over the last decade. The antitumor immune response combines innate and adaptive immune system elements [4]. Tumors, on the other hand, can harness this response and use it to evade the immune system in a variety of ways, including maintaining an immunosuppressive milieu or inducing cytotoxic cell malfunctions. An immunosuppressive tumor immune microenvironment (TIME) is marked by the existence of regulatory T cells (Treg), immunosuppressive myeloid cells including tumor-associated macrophages (TAMs), and inhibitory B cells [5]. Immune checkpoint activation, which includes coinhibitory substances, prevents effector cell activation and is crucial for tumor immune evasion [6]. Cancer treatment has been transformed by the development of immune checkpoint inhibitor (ICI)-based therapy, which has led to longterm responses and improved survival in a wide spectrum of cancers. However, ICIs have not been very effective against many solid tumors. Checkpoint proteins expressed by immune cells or tumor cells serve as targets for ICI monoclonal antibodies (mAbs), which elicit a robust immunological response from cytotoxic T lymphocytes (CTLs) [7]. Moreover, ICI therapy has shown to be effective in a subset of patients with a range of cancers, including HCC. Anti-PDL1 antibody atezolizumab and the VEGF neutralizing antibody bevacizumab are now the standard therapies for HCC [8]. Herein, we explored the rationale, molecular basis, and underlying preclinical evidence for immunotherapies in HCC, along with existing immunological clinical research.

## **2. Overview of immune components**
