Yufei Wang

Hepatitis B virus (HBV) infection is a major driver of hepatocarcinogenesis. Ferroptosis is a type of iron-mediated cell death that can suppress liver transformation. Previous studies have linked HBV to ferroptosis in liver fibrosis and acute liver failure. However, whether ferroptosis is involved in HBV-mediated liver cancer is poorly understood. Here, we identified heat shock protein family A member 8 (HSPA8) as a crucial host factor that modulates HBV replication and ferroptosis in liver cancer. Hepatitis B X protein (HBx) upregulated HSPA8 by coactivating the transcription factor heat shock factor 1 (HSF1) in cells. HSPA8 enhanced HBV replication by recruiting hepatitis B core protein (HBc) to the HBV covalently closed circular DNA (cccDNA) minichromosome, forming a positive feedback loop. Moreover, HSPA8 suppressed ferroptosis in liver cancer cells by upregulating the expression of SLC7A11/GPX4 and decreasing erastin-mediated reactive oxygen species and Fe2+ accumulation in cells in vitro and in vivo. Inhibition of HSPA8 reduced the growth of HBV-positive liver tumors and increased sensitivity to erastin. In conclusion, HBx-elevated HSPA8 regulates both HBV replication and ferroptosis in liver cancer. Targeting HSPA8 could be a promising strategy for controlling HBV and hepatocarcinogenesis. SIGNIFICANCE: HBV-induced upregulation of HSPA8 promotes hepatocarcinogenesis by suppressing ferroptosis and stimulating HBV replication, identifying HSPA8 as a potential therapeutic target in liver cancer.

T-cell-mediated antitumor immunity. Notably, combining the PRMT5 methyltransferase inhibitor GSK591 with PD-L1 blockade efficiently inhibited liver cancer growth and improved overall survival in mice. Collectively, our findings reveal the immunosuppressive role and mechanism of PRMT5 in liver cancer and highlight that targeting PRMT5 could boost checkpoint immunotherapy efficacy.

BACKGROUND: Immunotherapy that targets immune checkpoints has achieved revolutionary success, but its application in solid tumors remains limited, highlighting the need for reliable enhancement of the efficacy of immunotherapy. Golgi protein 73 (GP73), a Golgi membrane protein, has been implicated in various cellular processes, including immune regulation. Recent studies suggested that GP73 may play a role in modulating the immune response in patients with cancer. In this study, we investigated the mechanism by which GP73 regulates T-cell-mediated antitumor immunity within the tumor microenvironment. METHODS: We used T-cell specific GP73 knockout mice to establish MC38 and B16 tumor models to investigate the impact of GP73-deficient T cells on tumor growth. Single-cell sequencing was subsequently employed to classify tumor-infiltrating immune cells and assess changes in cytokines and metabolic genes. Through RNA sequencing, real-time quantitative PCR, western blotting, flow cytometry, seahorse analysis, glucose uptake, and L-lactic acid secretion assays, we explored how GP73 regulates hypoxia-inducible factor 1α (HIF-1α) to influence T-cell antitumor functionality. Furthermore, we established adoptive transfer experiments to study the ability of GP73-overexpressing T cells to combat tumors. Blood samples of patient with clinical tumor were collected to assess the relationship between immunotherapy efficacy and T-cell GP73 levels. RESULTS: In this study, the absence of GP73 in mouse T cells promoted tumor growth and metastasis, accompanied by a decrease in the proportion of cytotoxic CD8+T cell subsets infiltrating the tumor and an increase in exhausted CD8+ T-cell subsets. Further analysis revealed that the effector function of CD8+T cells in tumors relies on glycolysis regulated by HIF-1α rather than immune checkpoints. GP73-deficient T cells exhibit severely impaired glycolysis in hypoxic environments, whereas ectopic GP73 expression restores HIF-1α levels. In adoptive immunotherapy, overexpression of GP73 in T cells inhibits tumor growth. In cytotoxicity assays, knockdown of GP73 affected the ability of CD8+T cells to kill target cells. Clinically, tumor immunotherapy partial response patients present significantly elevated levels of GP73 expression in T cells. CONCLUSIONS: These findings reveal the role of GP73 in regulating T-cell glycolysis and may lead to new therapeutic strategies for the prognosis and treatment of clinical tumor immunotherapy.

The Fc fragment of IgG binding protein (FCGBP) has been confirmed to play an important role in various cancers. However, the specific role of FCGBP in hepatocellular carcinoma (HCC) remains undefined. Thus, in this study, the enrichment analyses (Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis) of FCGBP in HCC and extensive bioinformatic analyses using data of clinicopathologic characteristics, genetic expression and alterations, and immune cell infiltration were perfomed. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to verify the expression of FCGBP in both HCC tissues and cell lines. The subsequent results confirmed thatFCGBP overexpression positively correlated with poor prognosis in patients with HCC. Additionally, FCGBP expression could effectively distinguish tumor tissues from normal tissues, which was verified by qRT-PCR. The result was further confirmed by using HCC cell lines. The time-dependent survival receiver operator characteristic curve exhibited the strong ability of FCGBP to predict survival in patients with HCC. Additionally, we revealed the strong relationship between FCGBP expression and a number of classic regulatory targets and classical oncogenic signaling pathways of tumors. Finally, FCGBP was involved in the regulation of immune infiltration in HCC. Therefore, FCGBP has potential value in the diagnosis, treatment, and prognosis of HCC and may be a potential biomarker or therapeutic target.

<p>Supplementary materials and methods, Supplementary figures, Supplementary figure legends, Supplementary tables</p>