Liver cancer has the fourth highest mortality rate of all cancers worldwide, with hepatocellular carcinoma (HCC) being the most prevalent subtype. Despite great advances in systemic therapy, such as molecular-targeted agents, HCC has one of the worst prognoses due to drug resistance and frequent recurrence and metastasis. Recently, new therapeutic strategies such as cancer immunosuppressive therapy have prolonged patients’ lives, and the combination of an immune checkpoint inhibitor (ICI) and VEGF inhibitor is now positioned as the first-line therapy for advanced HCC. Since the efficacy of ICIs depends on the tumor immune microenvironment, it is necessary to elucidate the immune environment of HCC to select appropriate ICIs. In this review, we summarize the findings on the immune microenvironment and immunosuppressive approaches focused on monoclonal antibodies against cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1 for HCC. We also describe ongoing treatment modalities, including adoptive cell transfer-based therapies and future areas of exploration based on recent literature. The results of pre-clinical studies using immunological classification and animal models will contribute to the development of biomarkers that predict the efficacy of immunosuppressive therapy and aid in the selection of appropriate strategies for HCC treatment.

Liver cancer is the fourth leading cause of cancer deaths globally, of which hepatocellular carcinoma (HCC) is the major subtype. Viral hepatitis B and C infections, alcohol abuse, and metabolic disorders are multiple risk factors for liver cirrhosis and HCC development. Although great therapeutic advances have been made in recent decades, the prognosis for HCC patients remains poor due to late diagnosis, chemotherapy failure, and frequent recurrence. MicroRNAs (miRNAs) are endogenous, non-coding RNAs that regulate various molecular biological phenomena by suppressing the translation of target messenger RNAs (mRNAs). miRNAs, which often become dysregulated in malignancy, control cell proliferation, migration, invasion, and development in HCC by promoting or suppressing tumors. Exploring the detailed mechanisms underlying miRNA-mediated HCC development and progression can likely improve the outcomes of patients with HCC. This review summarizes the molecular and functional roles of miRNAs in the pathogenesis of HCC. Further, it elucidates the utility of miRNAs as novel biomarkers and therapeutic targets.

Hepatocellular carcinoma (HCC) is the seventh most frequent cancer and the fourth leading cause of cancer mortality worldwide. Despite substantial advances in therapeutic strategies, the prognosis of late-stage HCC remains dismal because of the high recurrence rate. A better understanding of the etiology of HCC is therefore necessary to improve outcomes. MicroRNAs (miRNAs) are small, endogenous, noncoding, single-stranded RNAs that modulate the expression of their target genes at the posttranscriptional and translational levels. Aberrant expression of miRNAs has frequently been detected in cancer-associated genomic regions or fragile sites in various human cancers and has been observed in both HCC cells and tissues. The precise patterns of aberrant miRNA expression differ depending on disease etiology, including various causes of hepatocarcinogenesis, such as viral hepatitis, alcoholic liver disease, or nonalcoholic steatohepatitis. However, little is known about the underlying mechanisms and the association of miRNAs with the pathogenesis of HCC of various etiologies. In the present review, we summarize the key mechanisms of miRNAs in the pathogenesis of HCC and emphasize their potential utility as valuable diagnostic and prognostic biomarkers, as well as innovative therapeutic targets, in HCC diagnosis and treatment.

Hepatocellular carcinoma (HCC) is the most common primary liver tumor and is often diagnosed at an unresectable advanced stage. Systemic chemotherapy as well as transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC) are used to treat advanced HCC. TACE and HAIC have long been the standard of care for patients with unresectable HCC but are limited to the treatment of intrahepatic lesions. Systemic chemotherapy with doxorubicin or chemohormonal therapy with tamoxifen have also been considered, but neither has demonstrated survival benefits. In the treatment of unresectable advanced HCC, cisplatin is administered transhepatic arterially for local treatment. Subsequently, for cisplatin-refractory cases due to drug resistance, a shift to systemic therapy with a different mechanism of action is expected to produce new antitumor effects. Cisplatin is also used for the treatment of liver tumors other than HCC. This review summarizes the action and resistance mechanism of cisplatin and describes the treatment of the major hepatobiliary cancers for which cisplatin is used as an anticancer agent, with a focus on HCC.

Primary liver cancer is the sixth most common cancer and the third most common cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is a major histologic type with a poor prognosis owing to the difficulty in early detection, the chemotherapy resistance, and the high recurrence rate of the disease. Despite recent advancements in HCC prevention and diagnosis, over 50% of patients are diagnosed at Barcelona Clinic Liver Cancer Stage B or C. Systemic therapies are recommended for unresectable HCC (uHCC) with major vascular invasion, extrahepatic metastases, or intrahepatic lesions that have a limited response to transcatheter arterial chemoembolization, but the treatment outcome tends to be unsatisfactory due to acquired drug resistance. Elucidation of the mechanisms underlying the resistance to systemic therapies and the appropriate response strategies to solve this issue will contribute to improved outcomes in the multidisciplinary treatment of uHCC. In this review, we summarize recent findings on the mechanisms of resistance to drugs such as sorafenib, regorafenib, and lenvatinib in molecularly targeted therapy, with a focus on epigenetic regulation and the tumor microenvironment and outline the approaches to improve the therapeutic outcome for patients with advanced HCC.

Systemic therapy for unresectable hepatocellular carcinoma (HCC) has progressed with the development of multiple kinases, such as vascular endothelial growth factor (VEGF) signaling, targeting cancer growth and angiogenesis. Additionally, the efficacy of sorafenib, regorafenib, lenvatinib, ramucirumab, and cabozantinib has been demonstrated in various clinical trials, and they are now widely used in clinical practice. Furthermore, the development of effective immune checkpoint inhibitors has progressed in systemic therapy for unresectable HCC, and atezolizumab + bevacizumab (atezo/bev) therapy and durvalumab + tremelimumab therapy are now recommended as first-line treatment. Atezo/bev therapy, which combines an anti-programmed cell death 1 ligand 1 antibody with an anti-VEGF antibody, is the first cancer immunotherapy to demonstrate efficacy against unresectable HCC. With the increasing popularity of these treatments, VEGF inhibition is attracting attention from the perspective of its anti-angiogenic effects and impact on the cancer-immune cycle. In this review, we outline the role of VEGF in the tumor immune microenvironment and cancer immune cycle in HCC and outline the potential immune regulatory mechanisms of VEGF. Furthermore, we consider the potential significance of the dual inhibition of angiogenesis and immune-related molecules by VEGF, and ultimately aim to clarify the latest treatment strategies that maximizes efficacy.