Liver transplantation (LT) is a life-saving treatment for patients with end-stage liver disease and hepatocellular carcinoma (HCC). Advances in surgical techniques and immunosuppressive regimens have markedly improved early post-transplant survival. However, long-term outcomes remain compromised by HCC recurrence, chronic rejection, metabolic complications, and de novo malignancies. Recurrence of HCC after LT remains a major clinical challenge, with available prognostic models providing limited accuracy in risk stratification. Simultaneously, systemic therapies for unresectable HCC have rapidly advanced, particularly with immune checkpoint inhibitors (ICIs), providing new opportunities and unique challenges in transplant settings. With ICIs carrying a risk of acute and potentially fatal rejection and lacking controlled data on efficacy or safety in the post-transplant setting, tyrosine kinase inhibitors currently represent a standard option for post-transplant recurrence. Novel biomarkers, such as donor-derived cell-free DNA and the gut microbiome, are emerging as potential tools to refine risk stratification and guide immunosuppression. Furthermore, innovative immunotherapies, including oncolytic viruses and mRNA vaccines, are being explored as tumor-specific approaches. Collectively, these advances may reshape future management of LT recipients.
Distinct tumor immune microenvironment modulation by anti-PD-1/PD-L1, VEGF, and CTLA-4 blockade provides a rationale for triplet therapy in hepatocellular carcinoma Hideki Iwamoto, Hironori Koga, Takumi Kawaguchi Clinical and Molecular Hepatology.2026; 32(1): e38. CrossRef
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Distinct tumor immune microenvironment modulation by anti-PD-1/PD-L1, VEGF, and CTLA-4 blockade provides a rationale for triplet therapy in hepatocellular carcinoma Hideki Iwamoto, Hironori Koga, Takumi Kawaguchi Clinical and Molecular Hepatology.2026; 32(1): e38. CrossRef
Correspondence to editorial 2 on “Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: insights from the IMbrave150 trial” Sun Young Yim, Sung Hwan Lee, Ji Hoon Kim, Sunyoung S Lee, Ahmed O Kaseb, Ju-Seog Lee Clinical and Molecular Hepatology.2025; 31(1): e84. CrossRef
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Distinct tumor immune microenvironment modulation by anti-PD-1/PD-L1, VEGF, and CTLA-4 blockade provides a rationale for triplet therapy in hepatocellular carcinoma Hideki Iwamoto, Hironori Koga, Takumi Kawaguchi Clinical and Molecular Hepatology.2026; 32(1): e38. CrossRef
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Striking advances in systemic therapy for unresectable advanced hepatocellular carcinoma (HCC) have improved the average prognosis of patients with HCC. As a result, the guidelines for the treatment of HCC have changed significantly. However, various issues have emerged in clinical practice. First, there is no established biomarker that can predict response to systemic therapy. Second, there is no established treatment regimen after primary systemic therapy, including combined immunotherapy. Third, there is no established treatment regimen for intermediate-stage HCC. These points make the current guidelines ambiguous. In this review, we present the Japanese guidelines for the diagnosis and treatment of HCC based on the latest evidence; introduce various efforts mainly in Japanese real-life practice to update these guidelines; and present our perspectives on future guidelines.
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Hepatocellular carcinoma (HCC) is usually accompanied by chronic liver damage, which sometimes influences the selection of HCC treatment. The Barcelona Clinic Liver Cancer (BCLC) staging system, which was first introduced in 1999, is the most commonly used worldwide. Although the intermediate-stage (BCLC stage B) includes the largest number and heterogeneous HCC patients, the recommended treatment option is transarterial chemoembolization (TACE) only. However, recent progress in radical treatments such as hepatic resection, liver transplantation, radiation therapy, and percutaneous therapy has made it possible to treat selected patients with BCLC stage B HCC. Radical treatments are expected to prolong survival time. To-date, TACE has also progressed. In addition to conventional TACE, balloon-occluded TACE and drug-eluting beads TACE are available. These new modalities of TACE will improve therapeutic efficacy and reduce adverse events. One of the most serious concerns of TACE is that repeated TACE reduces the treatment effect and induces liver function impairment. The decision on when TACE should be interrupted is complex. Many molecular targeted agents are now available, and immune checkpoint inhibitors will soon be available for HCC patients with Child-Pugh class A worldwide. Under these circumstances, in patients with TACE unsuitability, switching to molecular targeted agents before deterioration of liver function might improve the prognosis compared to repeated TACE. We should pay attention to stop TACE in TACE-unsuitable HCC patients as it can induce the deterioration of liver function.
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