Hepatitis D virus (HDV) is a satellite RNA virus of the hepatitis B virus (HBV) infecting an estimated 12 million people worldwide. Chronic HDV infection is causing the most severe form of chronic viral hepatitis, leading to a rapid progression of chronic inflammation to fibrosis, cirrhosis, liver decompensation and cancer. The detailed mechanisms responsible for HDV pathogenicity and its contribution to the development of hepatocellular carcinoma (HCC) are not clearly understood. This review aims to summarize the current knowledge of HDV-induced injuries, which gradually accumulate and increase the oncogenic pressure in the liver. Here, we provide a comprehensive yet concise overview of the following topics: (1) virus sensing and innate responses, (2) molecular basis of HDV pathogenesis, and (3) pathogenesis of chronic HDV infection in patients. We summarize the compelling evidence of the direct and indirect contributions of HDV to the development of HCC, which is driven by the rapid progression to liver cirrhosis. These results led to the classification of HDV as a group 1 carcinogenic agent in 2025 and emphasize the urgent need for improved antiviral and chemopreventive treatments. In addition, it highlights the necessity of routine HDV screening in patients with chronic hepatitis B and intensified HCC surveillance in patients with chronic hepatitis D.

Background and Aims: Hepatocellular carcinoma (HCC) is the most common form of liver cancer and is a major global health burden, ranking sixth in incidence and third in cancer-related mortality. Despite therapeutic advances, treatment options for advanced liver disease and HCC are limited, and strategies to prevent HCC development are lacking. To address the urgent need for preventive strategies, we identified aripiprazole, an oral atypical antipsychotic, as a candidate for HCC chemoprevention. Approach and Results: Analyses of clinical liver tissues showed that aripiprazole targets are expressed in different liver cell compartments, including fibroblasts, macrophages, and epithelial cancer cells, and that target gene expression is associated with fibrotic liver diseases and HCC. In a rat model of MASH-induced HCC induced by choline-deficient L-amino acid-defined high-fat diet, aripiprazole prevents liver disease progression and HCC development by modulating fibrogenesis-related pathways and inflammation. Mechanistically, aripiprazole exerts antifibrogenic and anti-inflammatory effects by modulating the phenotype of liver fibroblasts and macrophages. Moreover, perturbation studies in cancer cell models showed that aripiprazole prevents tumor initiation and reduces cell proliferation via inhibition of the cMET and ERK pathways and perturbation of mitochondrial functions. Finally, treatment of patient-derived tumor spheroids demonstrated that aripiprazole modulates immune responses in the tumor microenvironment. Conclusions: Collectively, these findings suggest that treatment with aripiprazole is a clinically relevant approach for HCC chemoprevention.

Cholangiocarcinoma (CCA) is an adenocarcinoma of the hepatobiliary system that has recently risen in incidence and mortality with unsatisfactory treatment options. Claudin-1 (CLDN1) is a transmembrane protein expressed in tight junctions and exposed on the cell surface in liver fibrosis and cancer. Using single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics of tissues of patients with CCA, we show that CLDN1 expression is up-regulated in cancer cells and is associated with stemness and cell fate. Genetic gain-of-function studies in CCA orthotopic in vivo mouse models showed decreased survival and enhanced tumor growth, unraveling a functional role of CLDN1 as an oncogenic driver. Targeting exposed nonjunctional CLDN1 using highly specific CLDN1 monoclonal antibodies (mAbs) inhibited tumor growth across CCA CDX and PDX mouse models and patient-derived CCA organoids, including tumors with medium or low CLDN1 expression. Moreover, antibody treatment inhibited tumor cell migration, invasion, and extrahepatic metastasis. Mechanistically, targeting exposed cell surface CLDN1 on CCA tumors using mAbs inhibited Notch1 and TROP2/STAT3 signaling pathways, resulting in decreased cancer cell stemness and epithelial-to-mesenchymal transition. Loss-of-function studies using CRISPR-Cas9 and RNAi combined with rescue and confocal imaging studies confirmed the functional and mechanistic role of these pathways. In conclusion, these results uncover CLDN1 as a previously undiscovered CCA driver and therapeutic target, paving the way for the clinical development of CLDN1 mAbs to improve the dismal outcome of patients with advanced CCA.

Chronic hepatitis B virus (HBV) infection remains a major cause of cirrhosis and hepatocellular carcinoma (HCC) worldwide, with more than 250 million people living with chronic infection despite effective prophylactic vaccination. While current treatments provide durable suppression of viral replication and reduce liver-related complications, they rarely achieve functional cure, defined as sustained hepatitis B surface antigen (HBsAg) loss after treatment cessation. Viral persistence is maintained by intrahepatic covalently closed circular DNA and HBV DNA integration, which sustain antigen production and contribute to immune dysfunction. This review summarizes current understanding of HBV immunopathogenesis across acute resolution and chronicity, emphasizing the compartmentalized and tolerogenic liver microenvironment, impaired innate sensing, and progressive dysfunction of HBV-specific B- and T-cell responses, including exhaustion phenotypes shaped by antigen specificity and intrahepatic priming. We also discuss immune correlates associated with functional cure, including partial restoration of polyfunctional HBV-specific T cells and intrahepatic immune remodeling. Finally, we discuss human clinical trials of immune-based therapies highlighting emerging combination strategies designed to couple antigen reduction with immune restauration, defined as the recovery of functional HBV-specific antiviral responses. Collectively, preclinical and clinical data suggest that achieving durable off-treatment control will likely require approaches that address both viral replication, antigen burden and HBV-specific immune responses.

Abstract The lack of effective anti-hepatitis B virus (HBV) therapies highlights the need for a new type of treatment that targets different stages of the viral life cycle. The HBV core protein (HBc) is a critical component of this cycle. Various capsid assembly modulators (CAMs) have been developed to target the HBc and inhibit HBV replication. We recently described a subset of capsid assembly modulators (CAMs) that induce the formation of aberrant structures from the HBc in the nucleus, leading to cell death via annexin A1 (ANXA1)-driven apoptosis. Thus, we further elucidated the mechanism of HBc aggregation in the nucleus, with a particular focus on the interplay between nuclear HBc aggregates and PML nuclear bodies. We found that long-term treatment with CAM-A induced the formation of enlarged PML bodies, approximately 1–2 µm in diameter, that accumulated aggregated HBc. PML silencing in HBc-overexpressing HepG2-NTCP cells led to a dramatic increase in apoptosis following CAM-A-induced HBc aggregation, which was associated with elevated ANXA1. Next, we showed that PML nuclear bodies orchestrate proteasomal degradation of nuclear HBc aggregates via sumoylation-dependent recruitment of RNF4. Collectively, our results suggest that PML nuclear bodies act as storage compartments for aggregated HBc proteins in the nucleus, thereby counteracting the apoptotic elimination of cells. Further study of PML function and the targeting of PML nuclear bodies in HBV-infected hepatocytes could reveal new ways to enhance the effectiveness of CAMs.

Abstract Malignant cutaneous melanoma is a highly aggressive cancer responsible for the majority of skin cancer-related deaths with increasing prevalence world-wide. While early-stage melanoma can be efficiently treated by surgery, the treatment of advanced melanoma with immune checkpoint (ICT) therapy remains unsatisfactory with a large number of patients displaying intrinsic resistance or developing resistance over time. A key therapeutic challenge is tumour heterogeneity with melanoma cells existing in multiple states with differing proliferative and invasive capacities. The transmembrane protein Claudin-1 (CLDN1) exhibits a dual role as tight junction protein regulating epithelial barrier function and as a regulator of epithelial-to-mesenchymal transition (EMT), a hallmark of fibrotic disease and cancer. Analyses of public TCGA and TIDE patient datasets showed that CLDN1 is preferentially expressed in mesenchymal melanoma cells and correlates with poor survival of metastatic melanoma and of ICT treated patients. In accordance, CLDN1 expression is associated with an immune-depleted tumour microenvironment (TME). Using gain and loss-of-function studies in human melanoma spheroids and xenografts in syngeneic mouse models, we define two critical roles for CLDN1 in melanoma, a requirement for growth of mesenchymal melanoma cells and the ability to reprogram a TME depleted in cytotoxic CD8 T cells that promotes tumour growth. CLDN1 antibody targeting further restored an immune-infiltrated TME to inhibit tumour growth and cooperation with anti-PD-1 ICT. Collectively, our data show that CLDN1 plays an important functional role melanoma and is a candidate target for antibody-based therapies. Citation Format: Antonin Lallement, Frank Jühling, Zeina Nehme, Bujamin Vokshi, Guillaume Davidson, Emilie Crouchet, Thomas F. Baumert, Irwin Davidson. Claudin-1 modulates the melanoma immune microenvironment to promote tumor growth and is a candidate therapeutic target for advanced melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB085.

The ECM is a dynamic component of the tumor microenvironment with a critical role in cancer progression, invasion, metastasis, immune exclusion, and response to therapy. Recent advances in proteomic analyses investigating the insoluble ECM fractions (termed “matrisome analysis”), along with single-cell RNA sequencing and spatial transcriptomics, have revealed cancer-specific patterns of ECM remodeling. These studies have identified a panel of recurrently upregulated ECM proteins, including annexin A1, fibrillin-1, fibronectin, periostin, and tenascin-C, actively contributing to tumor growth, invasion, angiogenesis, and immune exclusion. The expression of the cancer-associated ECM is largely driven by cancer-associated fibroblasts (CAFs), whose molecular diversity has been dissected through single-cell profiling and consolidated in emerging CAF atlases across cancers. By investigating the matrisome composition and CAF heterogeneity, these studies have unraveled the pivotal role of the stroma in shaping tumor biology. Based on these discoveries, ECM proteins and CAFs are now being explored as biomarkers and therapeutic targets. Future integration of multi-omics datasets with clinical outcomes will help to translate these insights into novel biomarkers for patient stratification and stroma-directed therapeutic interventions.

Claudin-1 (CLDN1), a tight junction protein overexpressed and mis-localized in colorectal cancer (CRC), plays a critical role in tumor progression, stemness, and therapy resistance. Integrative analyses of bulk and single-cell transcriptomic datasets revealed that CLDN1 is enriched in stem-like CRC cells, increases during metastatic progression, and is associated with microsatellite stable disease. High CLDN1 expression correlates with epithelial-to-mesenchymal transition and activation of oncogenic pathways including AKT/mTOR, Myc, and NF-κB. Here, we evaluate the therapeutic efficacy of an investigational humanized monoclonal antibody (H3L3) directed against overexpressed non-junctional CLDN1 in preclinical models of CRC. In xenograft mouse models and patient-derived organoids (PDOs), CLDN1 mAb significantly reduced tumor growth in CLDN1-expressing tumors. Mechanistically, CLDN1 mAb disrupted CLDN1-mediated signaling, notably inhibiting the AKT/mTOR pathway. CRISPR-mediated CLDN1 knockout abolished H3L3 efficacy, confirming target specificity. Transcriptomic analysis of PDOs treated with H3L3 revealed broad suppression of stemness, oncogenic signaling, and hallmark cancer pathways. Single-cell analysis further demonstrated that targeting CLDN1 modulates cellular plasticity, driving stem-like tumor cells toward a more differentiated epithelial phenotype. Together, these findings establish anti-CLDN1 monoclonal antibodies as a promising therapeutic approach for CRC. The selective binding of CLDN1 mAb to tumor-associated exposed and overexpressed CLDN1, along with its capacity to inhibit key oncogenic pathways and reprogram cancer cell states including tumors with different mutations conferring resistance to standard of care, underscores its potential to improve treatment outcomes in patients with CLDN1-expressing CRC.

Hepatitis D virus (HDV) causes the most severe form of chronic viral hepatitis, often leading to advanced liver disease and hepatocellular carcinoma. Viral cure is rarely achieved in infected patients. Interferon-alpha (IFN-α)-based therapies show suboptimal efficacy and low rates of sustained response, as reflected by their limited effect on HDV replication in vitro. Here, we show that HDV infection induces cellular resistance to IFN-α, marked by impaired STAT1 phosphorylation and reduced expression of interferon-stimulated genes (ISGs) in hepatocyte-like cells. This refractoriness depends on virus-induced innate immune activation, highlighting the role of HDV-induced ISG expression in regulating IFN signalling. We identify USP18 as a key mediator of IFN-α resistance in infected cells. Notably, ISG expression in response to type III IFN (IFN-λ) remains intact, consistent with USP18's selective inhibition of IFN-α signalling. Collectively, these findings reveal the molecular mechanism of IFN-α resistance in HDV-infected hepatocytes and provide a rationale for developing novel therapies against this major public health threat.

Claudins (CLDNs) are transmembrane proteins that contribute to the epithelial cell polarity and integrity of tight junctions in healthy tissues. CLDNs are frequently overexpressed across different solid tumours, and expression correlates with tumour subtype, grade and prognosis. Dysregulated CLDN expression modulates oncogenic signalling and contributes to tumour proliferation, epithelial-mesenchymal transition, stemness, fibrosis, immune modulation and therapeutic resistance. Owing to their frequent overexpression and functional role in cancer biology, CLDNs have emerged as attractive therapeutic targets. Their surface expression can be exploited to guide therapies into tumours. For example, a monoclonal antibody targeting the CLDN18.2 isoform has reached clinical approval, validating the potential of CLDN-directed approaches. Additional strategies such as antibody-drug conjugates, bispecific and trispecific antibodies and chimeric antigen receptor (CAR) T cells are in development for several CLDN family members. Targeting intracellular CLDN domains or their downstream signalling to disrupt their biological function may offer further promise. Here, we review the functional role of CLDN biology in solid tumours, summarize the clinical development of therapeutic approaches and discuss opportunities for biomarker-enriched patient selection. Collectively, we highlight CLDN targeting as a precision oncology approach relevant to multiple solid tumours.

Cancer cells require large quantities of glucose to ensure sufficient ATP production through glycolysis, and the liver may facilitate this glucose supply. A high-fat low-carbohydrate ketogenic diet (KD) could represent a strategy to reduce tumor growth. However, the molecular effects of carbohydrate restriction mediated by the KD and its hepatic impact remain poorly understood. To address this question, 6-wk-old FVB/N-Tg(MMTV-PyVT)634Mul/J mice, which develop spontaneous mammary tumors, were fed a standard chow diet (SD group) or a KD diet (KD group) until reaching the age of 12 wk. The effects of carbohydrate restriction were assessed by plasma analyses, as well as histological staining, RT-qPCR, and Western blotting in tumors and liver. We found that carbohydrate restriction reduced tumor growth by 46% and was associated with decreased expression of protumorigenic factors (Ang2, Hgf, and Mki67). Moreover, a decrease of metabolic enzymes (Pfk, Bdh1, and Scot1) highlighted the lack of metabolic flexibility of the tumor cells and underscored their strong dependency on glucose. Conversely, the liver exhibited a strong adaptive response with enhanced ketogenesis and gluconeogenesis, evidenced by elevated blood glucose and upregulation of Pepck, Foxo1, and CREB. A high-fat, low-carbohydrate diet exerts a dual metabolic effect: it suppresses tumor progression through local metabolic reprogramming but simultaneously enhances hepatic glucose production. This highlights the pivotal role of systemic glucose availability in tumorigenesis and underscores the need to consider liver metabolism when designing dietary interventions for cancer therapy.NEW & NOTEWORTHY We demonstrate that carbohydrate restriction alone slows breast tumor growth by limiting glucose availability and exposing the metabolic inflexibility of cancer cells. Despite an antitumor effect, carbohydrate restriction also triggers a robust hepatic compensatory response that increases endogenous glucose production. These findings provide important new insights for the design of metabolic interventions in oncology, highlighting the central role of liver-tumor metabolic cross talk and showing that dietary strategies should consider whole body glucose homeostasis.

Cancer cells rely on glycolysis and lactic fermentation for ATP production, inducing an abnormal glucose uptake in tumors. However, it is largely unknown whether the increased tumor glucose consumption affects overall body glucose homeostasis including perturbation of the liver glucose production pathways. The effect of mammary tumor development on the liver metabolism pathway was examined by using a mouse model based on FVB/N wild-type (WT-SD) and FVB/N-Tg(MMTV-PyVT)634Mul/J mice (Tg-SD), who develop spontaneous mammary tumors. Blood and livers were analyzed for metabolic changes, by measuring histological staining, signaling, and insulin sensitivity. Tg-SD mice developed mammary tumors with an average weight of 6 g, and cancer development increased total food intake without impacting body weight gain. Tumor development did not affect blood glycemia and lactate levels but increased insulin and homeostasis model assessment of insulin resistance (HOMA-IR) index (P = 0.06). In the liver, Tg-SD mice with tumors exhibited a decrease in glycogen content and an increase in gluconeogenesis gene expression, as G6pc, Pgc1α, and Foxo1 (P < 0.05), as well as Pepck and Ldha (P < 0.01). Moreover, the phosphorylation of AMPK and AKT was significantly decreased (P < 0.01 and P < 0.05, respectively). Surprisingly, liver fibrosis was markedly increased in Tg mice (P < 0.05) alongside elevated inflammatory gene expression, such as IL1β (P < 0.01) or IL6 (P < 0.05). Here, we found that the development of non-metastatic mammary tumors using the MMTV-PyMT mouse model disrupts liver function through the development of inflammation, fibrosis, and metabolic perturbation, including an increase in glucose production and insulin resistance. Finally, these observations unravel a previously unknown metabolic cross talk between the tumors and the liver.NEW & NOTEWORTHY This work demonstrates that the spontaneous development of non-metastatic mammary tumors triggers hepatic activation of endogenous glucose production pathways, coinciding with the onset of insulin resistance. This finding suggests a significant cross talk between tumors and the liver during tumorigenesis, aiming at enhancing glucose production to meet the elevated energy demands of the tumor. Understanding this interaction could provide insights into metabolic alterations associated with cancer and lead to potential therapeutic targets to inhibit tumor metabolism.

Chronic hepatitis B virus (HBV) infection is a global health problem as it is the major cause of liver fibrosis and its complications cirrhosis and hepatocellular carcinoma. The role of virus-host interactions in liver fibrosis and progression to cancer remains poorly understood. Here we show that HBV infection of permissive cells trigger pathways relevant for extracellular matrix (ECM) remodeling, which is a hallmark of liver fibrosis. We demonstrate that collagen VI (ColVI) is secreted from infected cells and induces a profibrotic phenotype in patient-derived myofibroblasts and identified HBV-induced AKT signaling as a driver of ColVI expression in HBV-infected cells. Consistently, ColVI is upregulated in the liver of HBV patients with fibrosis. Our results suggest a role of ColVI as a driver of HBV-associated liver disease and highlight the potential of ColVI as a biomarker candidate and therapeutic target in HBV-infected patients.