Background: The management of hepatocellular carcinoma (HCC) with high tumor burden and major portal vein tumor thrombosis (PVTT) remains a great challenge. The authors aimed to investigate the efficacy and safety of lenvatinib plus drug-eluting bead transarterial chemoembolization (DEB-TACE) and hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, fluorouracil and leucovorin (Len+DEB-TACE+HAIC) versus lenvatinib plus DEB-TACE (Len+DEB-TACE) for HCC greater than 7.0 cm accompanied with major PVTT. Materials and methods: This multicenter retrospective cohort study evaluated consecutive patients with HCC (> 7.0 cm) and major PVTT who received Len+DEB-TACE+HAIC (Len+DEB-TACE+HAIC group) or Len+DEB-TACE (Len+DEB-TACE group) between July 2019 and June 2021 from eight institutions in China. Objective response rate (ORR), time to progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were compared between the two groups by propensity score matching (PSM). Results: A total of 205 patients were included. After PSM, 85-paired patients remained in the study cohorts. Patients in the Len+DEB-TACE+HAIC group had higher ORR (61.2% vs. 34.1%, P < 0.001), longer TTP (median, 9.8 vs. 5.9 months, P < 0.001), and prolonged OS (median, 16.7 vs. 12.5 months, P < 0.001) than those in the Len+DEB-TACE group. The ORR and TTP of both intrahepatic tumor (ORR: 64.7% vs. 36.5%, P < 0.001; median TTP: 10.7 vs. 7.0 months, P < 0.001) and PVTT (ORR: 74.1% vs. 47.1%, P < 0.001; median TTP: 17.4 vs. 7.6 months, P < 0.001) were better in the Len+DEB-TACE+HAIC group than the Len+DEB-TACE group. The frequency of grade 3-4 TRAEs in the Len+DEB-TACE+HAIC group were comparable to those in the Len+DEB-TACE group (38.8% vs. 34.1%, P = 0.524). Conclusion: The addition of HAIC to Len+DEB-TACE significantly improved ORR, TTP, and OS over Len+DEB-TACE with an acceptable safety profile for large HCC with major PVTT.

Background: It is now understood that HBV can induce innate and adaptive immune response disorders by affecting immunosuppressive macrophages, resulting in chronic HBV infection. However, the underlying mechanism is not fully understood. Dysregulated protein acetylation can reportedly influence the differentiation and functions of innate immune cells by coordinating metabolic signaling. This study aims to assess whether HBV suppresses macrophage-mediated innate immune responses by affecting protein acetylation and to elucidate the underlying mechanisms of HBV immune escape. Methods: We investigated the effect of HBV on the acetylation levels of human THP-1 macrophages and identified potential targets of acetylation that play a role in glucose metabolism. Metabolic and immune phenotypes of macrophages were analyzed using metabolomic and flow cytometry techniques. Western blot, immunoprecipitation, and immunofluorescence were performed to measure the interactions between deacetylase and acetylated targets. Chronic HBV persistent infected mice were established to evaluate the role of activating the tricarboxylic acid (TCA) cycle in macrophages for HBV clearance. Results: Citrate synthase/pyruvate dehydrogenase complex hyperacetylation in macrophages after HBV stimulation inhibited their enzymatic activities and was associated with impaired TCA cycle and M2-like polarization. HBV downregulated Sirtuin 3 (SIRT3) expression in macrophages by means of the toll-like receptor 2 (TLR2)-NF-κB- peroxisome proliferatoractivated receptor γ coactivator 1α (PGC-1α) axis, resulting in citrate synthase/pyruvate dehydrogenase complex hyperacetylation. In vivo administration of the TCA cycle agonist dichloroacetate inhibited macrophage M2-like polarization and effectively reduced the number of serum HBV DNA copies. Conclusions: HBV-induced citrate synthase/pyruvate dehydrogenase complex hyperacetylation negatively modulates the innate immune response by impairing the TCA cycle of macrophages. This mechanism represents a potential therapeutic target for controlling HBV infection.

Purpose: Hepatocellular Carcinoma (HCC) features a complex pathophysiology and unpredictable immunosuppressive microenvironment, which limit the effectiveness of traditional therapies and lead to poor patient outcomes. Understanding the immune characteristics of HCC is essential for elucidating the immune microenvironment and developing more effective treatments. This study investigates the role of Peptidyl-prolyl isomerase H (PPIH) in HCC by analyzing its expression, prognosis, methylation levels, and relationship with immune cell infiltration. Methods: We utilized bulk sequencing and clinical data from UCSC Xena and the GTEx database for preprocessing and subsequent differential expression analysis of PPIH in tumor and adjacent normal tissues, evaluating prognostic parameters like overall survival and disease-free interval between low and high PPIH expression groups. Immune infiltration was analyzed via CIBERSORT and ssGSEA, while DNA methylation and somatic mutation analyses were performed using MExpress and "maftools", respectively, alongside in vitro and in vivo experiments to assess PPIH's functional roles. Results: Our findings indicated that PPIH is significantly upregulated in various cancer types, correlating with poor patient prognosis, increased somatic mutations, and altered gene methylation patterns. High PPIH levels were linked to enhanced T regulatory (Treg) cell infiltration and a decline in Th17 cell populations, impacting vital pathways related to DNA damage repair and tumor proliferation. Furthermore, PPIH knockdown in vitro led to reduced cell viability, proliferation, and invasion while promoting apoptosis. In vivo, PPIH knockdown repressed tumor growth and modified the immune microenvironment by attenuating Th17 cell infiltration and potentially increasing Treg cell accumulation. Conclusion: This study emphasizes PPIH's critical role in HCC progression by facilitating tumor growth and survival while modulating the immune landscape, thereby positioning PPIH as a potential therapeutic target for HCC management.