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.

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.

Background and Aim: This study aimed to elucidate the clinical importance of muscle volume loss (pre‐sarcopenia) in patients receiving lenvatinib as treatment for unresectable hepatocellular carcinoma (u‐HCC).Methods: Of 437 u‐HCC patients treated with lenvatinib at specific institutions in Japan between March 2018 and May 2020, 151 with available computed tomography imaging data from the time of lenvatinib introduction were enrolled. Pre‐sarcopenia was diagnosed based on a previously reported cut‐off value calculation formula [psoas muscle area at level of middle of third lumbar vertebra (cm²)/height (m)²]. Clinical features and prognostic factors for overall survival (OS) with inverse probability weighting were investigated retrospectively for their relationship with pre‐sarcopenia.Results: Cox hazard multivariate analysis showed alpha‐fetoprotein (≥400 ng/mL) (hazard ratio [HR] 2.271, P < 0.001), Barcelona Clinic Liver Cancer stage (C and D) (HR 1.625, P = 0.018), and positive for pre‐sarcopenia (HR 1.652, P = 0.042) to be significant prognostic factors. OS rates for the pre‐sarcopenia group (n = 41) were worse than those for the non‐pre‐sarcopenia group (n = 110) (0.5‐, 1‐, and 1.5‐year OS: 72.5%, 27.9%, and 7.0% vs 80.7%, 56.7%, and 46.1%, respectively; P < 0.001), as was progression‐free survival (P = 0.025). Time to stopping lenvatinib or disease progression was better in the non‐pre‐sarcopenia group (0.5‐, 1‐, and 1.5‐year OS: 48.0%, 24.5%, and 8.4% vs 20.0%, 10.3%, and 4.2%, respectively; P < 0.001). Also, the frequency of the adverse event appetite loss (any grade) was greater in the pre‐sarcopenia group (43.9% vs 18.2%, P = 0.003).Conclusion: Pre‐sarcopenia was shown to be a significant prognostic factor in patients treated with lenvatinib for u‐HCC.

This retrospective multicenter study analyzed 244 patients with unresectable hepatocellular carcinoma treated with lenvatinib (LEN) and atezolizumab + bevacizumab (Atezo + Bev) to examine the characteristics, treatment courses, and prognoses. The cases of patients who could achieve HCC downstaging from Barcelona Clinic Liver Cancer (BCLC) stage B or C to A or zero indicated the need for conversion therapy. The patients’ prognoses with and without conversion therapy were compared. Of the 244 patients, 12 (4.9%) underwent conversion therapy, six out of 131 (4.6%) were treated with LEN, and six out of 113 (5.3%) were treated with Atezo + Bev. Eleven patients (91.7%) with a modified albumin bilirubin (mALBI) grade 1 or 2a and BCLC-B stage showed significantly higher rates of transition during conversion therapy (p < 0.05). The patients undergoing conversion therapy had a significantly longer median overall survival rate than those receiving chemotherapy alone (1208 [1064–NA] vs. 569 [466–704] days, p < 0.01). A comparison of the patients who achieved a partial response with and without conversion was evaluated using propensity score matching to reduce the confounding factors, showing a significant survival benefit in the conversion group (1208 [1064–NA] vs. 665 days, p < 0.01). Among the patients with u-HCC who were treated with LEN and Atezo + Bev, those with mALBI 1 + 2a and BCLC-B were likely to achieve conversion therapy with downstaging.

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.

Introduction: Lack of an established methodology for post-progression systemic treatment following atezolizumab plus bevacizumab (Atez/Bev) administration is an important clinical issue. The present study aimed to elucidate the potential of lenvatinib as a second-line treatment option after Atez/Bev failure. Methods: From 2020 to 2022, 101 patients who received lenvatinib as second-line treatment were enrolled (median 72 years, males 77, Child-Pugh A 82, BCLC-A:B:C:D = 1:35:61:4), while 29 treated with another molecular targeting agent (MTA) during the period as second-line treatment were enrolled as controls. The therapeutic efficacy of lenvatinib given as second-line treatment was retrospectively evaluated. Results: Median progression-free survival/median overall survival for all patients was 4.4/15.7 months and for those with Child-Pugh A was 4.7 months/not-reached. When prognosis was compared with patients who received another MTA, there was no significant difference for PFS (3.5 months, p = 0.557) or OS (13.6 months, p = 0.992), and also no significant differences regarding clinical background factors. mRECIST findings showed that objective response and disease control rates in patients treated with lenvatinib were 23.9% and 70.4%, respectively (CR:PR:SD:PD = 3:14:33:21), while those shown by RECIST, ver. 1.1, were 15.4% and 66.2%, respectively (CR:PR:SD:PD = 1:10:36:24). Adverse events (any grade ≥10%) were appetite loss (26.7%) (grade 1:2:3 = 2:15:10), general fatigue (21.8%) (grade 1:2:3 = 3:13:6), protein in urine (16.8%) (grade 1:2:3 = 0:4:13), and hypertension (13.9%) (grade 1:2:3 = 1:8:5). Conclusion: Although lenvatinib treatment might not provide a pseudo-combination immunotherapy effect following Atez/Bev failure, lenvatinib when used as second-line treatment after Atez/Bev failure might be expected to be comparable as compared to its use as first-line treatment.