Hepatitis B virus (HBV) infection remains the most important risk factor for hepatocellular carcinoma (HCC) worldwide and nonalcoholic fatty liver disease (NAFLD) has developed as major etiology of chronic liver diseases, cirrhosis and eventually HCC in the last decades. Although nucleos(t)ide analogs are recommended as the first-line drug for patients with chronic hepatitis B, incomplete eradication of HBV serves as an obstacle for effective cure of chronic hepatitis B and even HCC. NAFLD refers to a spectrum of hepatic metabolic disorders, compromised with multi-system diseases. Considering the specificity of hepatocytes and enrichment of immune cells in liver, this review aims to summarize the mechanisms of direct pro-tumorigenesis to hepatocytes induced by HBV infection and abnormal lipid metabolism, and indirect oncogenic processes mediated by immune cells. We also discuss similarities and differences of immune cells between HBV- and NAFLD-HCC and finally focus on the novel immunotherapies concerning preclinical and clinical studies for liver cancer.

Hepatocellular carcinoma (HCC) is a deadly malignancy which typically occurs in the context of chronic liver inflammation. Chronic hepatitis B virus (HBV) infection is considered a major global cause of HCC development. At the moment, liver transplantation is the only curative modality for HBV-associated HCC. However, some patients develop HBV-HCC recurrence after liver transplantation, leaving them with very limited therapeutic options. Adoptive cell therapy with HBV-specific T cell receptor (TCR) that redirects T cells against HCC relapses has shown promising results in such HBV-HCC patients. In this mini-review, we discuss the application of this personalized T cell therapy, and highlight mRNA electroporation as an efficient tool for engineering safe and efficient TCR-redirected T cells for the treatment of liver transplant patients with HBV-HCC metastasis.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the liver, with poor prognosis and high mortality. Traditional treatments for patients with HCC have shown poor efficacy especially for advanced liver cancer. Compared with other organs, the liver has more natural immune cells such as Kupffer cells, natural killer cells and natural killer T cells. Immunotherapy for liver cancer has become the focus in current research. The theoretical basis of immunotherapy rests on immune tolerance and suppression in the tumor microenvironment. Common immunotherapy methods include vaccines, cytokines, adoptive cell therapies, immune checkpoint inhibitors, and oncolytic viruses. Compared with traditional treatment, immunotherapy can enhance the body’s immune function, delay tumor progression, and prolong survival. This article reviews the HCC microenvironment and immunotherapy both in the clinical and basic research aspects.

Most patients diagnosed with hepatocellular carcinoma (HCC) present with advanced or metastatic disease. The lack of therapeutic options in the treatment of advanced HCC accounts for its high mortality and recurrence rate. HCC is known as an immunogenic tumor, which develops in chronically inflamed livers. Anti-PD-1/PD-L1 antibodies (immune checkpoint inhibitors, ICB) were approved by the FDA to treat advanced HCC in patients previously treated with sorafenib as a second line. This has opened up a new era of anticancer treatment, although the response rate of HCC to anti-PD-1/PD-L1 antibodies is only around 20%. Other than ICB treatment, adoptive cell transfer, dendritic cell-based vaccines and oncolytic therapy are currently under clinical trials. In this review, different immunotherapy approaches for HCC is presented. Current knowledge on the mechanisms of action for each approach is discussed and relevant, ongoing clinical trials are presented. We also discuss the future of immunotherapy and combination treatment for HCC patients.

Hepatocellular carcinoma (HCC) is one of the most common solid tumors with poor clinical prognosis. Novel therapeutic regimens are urgently required for patients with advanced HCC. Both pre-clinical and clinical studies suggest immunotherapy as an attractive alternative for advanced HCC treatment. Natural killer (NK) cells and CD8⁺ T cells are the most important cytotoxic immune cells involved in cancer treatment and elimination. Reinvigorating the anticancer activity of NK and CD8⁺ T cells is the fundamental guarantee for the success of immunotherapy in advanced HCC treatment. Therefore, in this review, we aim to summarize the characteristics and roles of NK and CD8⁺ T cells in HCC development, describe the frontiers of immunotherapy for advanced HCC based on immune checkpoint inhibitors and adoptive cell transfer, and discuss their limitations and scope for future improvement.

Hepatocellular carcinoma (HCC) is the most lethal and common type of liver cancer with limited treatment options at the advanced stage. The use of immune checkpoint inhibitor (ICI) based immunotherapy is exponentially increasing in the treatment of patients with advanced solid tumors. The expression of immune checkpoints on tumor cells leading to lower activity of T-cells is one of the major mechanisms of immune escape. Checkpoint blockade immunotherapies with antibodies against PD-1, PD-L1 or CTLA-4 are being investigated in clinical trials in HCC patients. ICIs have improved survival in patients with inoperable advanced stage HCC where other curative treatments are not applicable. However, the response rates remain low with only a small subset of patients responding to this therapy. There is an unmet need to identify predictive markers to select those HCC patients who would benefit from ICI therapies. Importantly, epithelial-to-mesenchymal transition (EMT), a major process driving HCC invasion and metastasis by regulating the phenotypic cellular switching from epithelial to mesenchymal state, has been implicated as a resistance mechanism associated with ICI therapies. The role of EMT as a regulator of immune checkpoint molecule in HCC is just emerging. However, the consequence of EMT as a resistance mechanism in HCC patients undergoing ICI treatments remains unexplored. In this review, we summarize the recent clinical studies with ICIs in HCC and highlight the trials underway featuring novel monotherapies and combinatorial approaches based on immune and non-immune therapies. We will discuss the ongoing efforts to discover new immune checkpoint molecules in HCC as potential drug targets. We also highlight the role of EMT in facilitating therapy resistance in HCC treated with ICIs and discuss potential strategies to circumvent resistance in ICI treated HCC patients.