antibodies

2026-09-26 | Interleukin-11 Signaling in Liver Disease: Mechanisms, Cellular Crosstalk, and Therapeutic Potential.

The liver has a remarkable regenerative capacity, but persistent injury caused by drugs, metabolic dysfunction, alcohol, and chronic inflammation can overwhelm this process and promote fibrosis and hepatocellular carcinoma. Interleukin-11 (IL-11), a cytokine that signals through glycoprotein 130 (gp130), was historically considered hepatoprotective; however, accumulating experimental evidence predominantly identifies endogenous IL-11 as an amplifier of liver injury and maladaptive repair. In hepatocytes, IL-11 promotes oxidative stress, mitochondrial dysfunction, and cell death while limiting effective regeneration. In hepatic stellate cells, it sustains myofibroblastic activation and extracellular matrix production, while crosstalk with hepatocytes, macrophages, and the matrix reinforces a fibroinflammatory niche. In hepatocellular carcinoma, experimental and associative clinical evidence implicates IL-11 in tumor growth, invasion, metastatic colonization, postoperative recurrence, stromal remodeling, and immune suppression. These findings have supported the development of therapeutic strategies targeting the IL-11/IL-11RA axis, with the potential to provide broad therapeutic benefits across a wide spectrum of liver diseases. This review summarizes IL-11 regulation and signaling in liver disease; discusses its roles in liver injury, fibrosis, and hepatocellular carcinoma; and evaluates the opportunities and challenges of IL-11-targeted therapy.

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2026-06-26 | Immunometabolic Reprogramming in Hepatocellular Carcinoma Mechanisms, Biomarkers, and Therapeutic Implications.

Hepatocellular carcinoma (HCC) develops in a chronically inflamed and dysregulated liver metabolism, in which tumor progression and resistance to treatment are orchestrated by the changes in cellular metabolism and immune control. Growing evidence recognizes immunometabolic reprogramming as the two-way interaction of metabolic processes and immune cell capabilities as one of the major determinants of immune evasion and heterogeneity of treatment response in HCC. The review aims to comprehensively evaluate immunometabolic reprogramming in hepatocellular carcinoma, with a focus on its role in tumor progression, immune regulation, and its potential for biomarker identification and therapeutic targeting. Dysregulated glycolysis, lipid metabolism, amino acid utilization, and mitochondrial dysfunction contribute to remodeling of the tumor microenvironment and defects in antitumor immunity. Immunometabolic biomarkers derived from tumor tissue, immune cell states, circulating and liquid biopsy platforms, and metabolic imaging are critically examined for their clinical relevance and associations with disease outcomes and treatment responses. Besides, the role of different immunometabolic conditions on therapeutic efficacy, specifically within the frames of immune checkpoint-inhibitor-based and combination regimens, is addressed. Altogether, immunometabolic reprogramming is identified as a common framework of biomarker-based stratification and precision therapeutic techniques in hepatocellular carcinoma.

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2026-06-17 | ISG15 upregulation characterizes a PD-L1-associated immunosuppressive phenotype with CD8+ T-cell dysfunction in hepatocellular carcinoma.

Immune checkpoint inhibitors (ICIs) show promise in hepatocellular carcinoma (HCC) treatment, but clinical responses remain limited due to immune evasion. CD8+ T-cell dysfunction is a key mechanism of immune evasion in HCC. Interferon-stimulated gene 15 (ISG15), a ubiquitin-like modifier, is implicated in tumor progression, but its role in immune suppression in HCC is unclear. ISG15 expression was analyzed in the TCGA-LIHC cohort, and its correlation with prognosis, immune infiltration, and checkpoint-related gene expression was evaluated. Single-cell RNA sequencing identified ISG15 expression in CD8+ T-cell subsets. Immunohistochemistry and multiplex immunofluorescence were performed on clinical HCC samples, focusing on tumor recurrence. In vitro, ISG15 overexpression and knockdown models in HepG2 and MHCC97L cells assessed effects on CD8+ T-cell viability, cytokine production, and cytotoxic activity. PD-L1 blockade assays were performed in the ISG15-overexpression group to assess the functional involvement of PD-L1. ISG15 was upregulated in HCC and was associated with poor prognosis, higher TIDE scores, and increased immune checkpoint gene expression. Single-cell analysis identified ISG15-enriched CD8+ T-cell subsets with IFN/ISG-related and exhaustion-associated features. In co-culture assays, tumor-cell ISG15 overexpression was associated with reduced CD8+ T-cell viability, cytokine secretion, and cytotoxicity, together with increased PD-L1 expression and anti-apoptotic proteins. PD-L1 blockade partially restored CD8+ T-cell effector function. ISG15 is associated with an immunosuppressive phenotype in HCC and may represent a candidate biomarker and potential target for further investigation in HCC immunotherapy.

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2026-06-16 | Biallelic ARID1A Alterations: A Promising Novel Biomarker for Risk Stratification and Management in Pediatric Malignant Hepatocellular Tumors.

Somatic mutations and copy number alterations of the adenine-thymine (AT)-rich interactive domain-containing protein 1A (ARID1A), a tumor suppressor gene, are associated with poor prognosis in many cancers, including adult hepatocellular carcinomas (HCC). In this study, ARID1A protein expression, clinicopathologic features, and outcomes were investigated in 59 pediatric malignant hepatocellular tumors (2004 to 2022) relative to ARID1A mutation and copy number status. Additional studies were performed on the impact of the loss of ARID1A protein expression on genomic instability, immune-cell infiltration, and PD-L1 protein expression. Twenty-three of the 59 (38.9%) children with malignant hepatocellular tumors (age: 0.4 to 13.8 y, M:F=2:1) harbored ARID1A alterations (mutations and/or copy number alterations). Nine tumors (15.2%) with biallelic alterations (ARID1A -/-) showed higher metastasis at presentation (P=0.01), were frequently CHIC high-risk (P=0.05), had aggressive histology (HCN-NOS and HCC) (P=0.002), and were negative for ARID1A immunohistochemistry (IHC) (100%). ARID1A loss by IHC was 100% sensitive and 98% specific, with 90% positive and 100% negative predictive value for ARID1A -/- tumors. ARID1A-negative tumors showed higher chromosomal instability (P=0.04), immune infiltrates (P=0.005), and PD-L1 expression by IHC (P=0.05). Patients with both ARID1A-negative and ARID1A-negative/PD-L1-positive tumors showed the lowest disease-specific survival in the intermediate and high CHIC-risk and all PRETEXT subgroups (P=ns). The association of biallelic ARID1A alterations with high-risk features and poor outcomes identifies ARID1A as a potential new biomarker in the risk stratification of children with malignant hepatocellular tumors. ARID1A IHC is a reliable tool to identify these aggressive tumors. Associated PD-L1 expression may offer new therapeutic options via checkpoint inhibitors.

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2026-05-18 | Association of HAMP Expression and CD8+ T-Cell Infiltration With Atezolizumab-Bevacizumab Response in Hepatocellular Carcinoma.

Atezolizumab combined with bevacizumab is the standard first-line therapy for unresectable hepatocellular carcinoma; however, predictive biomarkers of therapeutic response remain undefined. We aimed to identify molecular features associated with therapeutic efficacy to develop personalized treatment strategies. Transcriptomic analyses were performed using public RNA-sequencing datasets of patients with hepatocellular carcinoma receiving anti-PD-L1-based therapy, comparing responders (complete response/partial response) with non-responders (stable disease/progressive disease). Differentially expressed genes and enriched pathways were identified using integrated differential expression and pathway analysis. For validation, RNA-sequencing was performed on institutional tumor samples (n = 6) underwent. Immunohistochemistry was performed on resected specimens (n = 9) to evaluate CD8+ tumor-infiltrating lymphocytes and hepcidin protein expression encoded by the HAMP gene. Group comparisons for the pre-specified immunohistochemistry endpoints were analyzed using exact Wilcoxon rank-sum tests with multiplicity control (Holm adjustment). Analysis of public datasets revealed distinct expression profiles in responders, enriched in immune-related and chemokine signaling pathways. Candidate genes, including HAMP, TAT, and HRG, were upregulated in responders. In institutional samples, HAMP expression was significantly higher in preoperatively treated tumors (p = 0.001). Immunohistochemistry demonstrated greater CD8+ tumor-infiltrating lymphocyte density (median 36.6 vs. 5.0 cells/high-power field; exact Wilcoxon p = 0.032) and higher HAMP immunoreactive scores (median 4 vs. 0.5; p = 0.032) in responders than in non-responders. Upregulation of HAMP and hepcidin protein expression, together with increased CD8+ T-cell infiltration, was associated with a favorable response to atezolizumab-bevacizumab in patients with hepatocellular carcinoma. HAMP may serve as a component of a composite biomarker predictive of therapeutic sensitivity, warranting validation in larger, multi-institutional cohorts.

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small molecules

2026-09-27 | Magnetoreceptor Promotes Hepatocellular Carcinoma Development and Blunts Sorafenib-Induced Ferroptosis by Regulating Iron Homeostasis.

Iron homeostasis plays a critical role in the pathogenesis and therapeutic management of hepatocellular carcinoma (HCC). Magnetoreceptor (MagR), also known as iron-sulfur cluster assembly protein 1 (ISCA1), is a conserved protein maintaining iron homeostasis, plays an undefined role in HCC. The present study aimed to elucidate MagR's functional involvement in HCC pathogenesis and sorafenib-induced ferroptosis, and to explore its therapeutic potential for HCC. Pan-cancer analyses showed that MagR was significantly upregulated in HCC tissues compared with normal liver tissues, accompanied with advanced stage and poor prognosis in patients. Functional experiments further demonstrated that MagR deficiency suppressed HCC cell proliferation, migration, and invasion while enhancing the sensitivity of these cells to sorafenib-induced ferroptosis, whereas overexpression of MagR had opposite effects. Mechanistically, MagR promoted HCC progression by sustaining cellular iron homeostasis and preserving mitochondrial function, and mediated ferroptosis sensitivity of HCC cells via regulating intracellular iron accumulation. Notably, in vivo studies showed that MagR ablation not only attenuated the growth of HCC xenograft tumors but also potentiated the antitumor efficacy of sorafenib. Collectively, these findings identify MagR as a potential therapeutic target for HCC and establish that therapeutic strategies targeting MagR could optimize sorafenib-based treatment regimens for this disease.

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2026-08-26 | Discovery of a novel 10-hydroxy-12-methyl-substituted evodiamine derivative with anti-hepatocellular carcinoma activity through multi-pathway modulation involving suppression of PKA/AKT signaling cascades and moderate Topo I inhibition.

Hepatocellular carcinoma (HCC) is a highly lethal malignancy with poor prognosis. The clinical benefits of small-molecule therapeutics represented by sorafenib remain limited, underscoring the urgent need to continuously invest in the discovery of novel anti-HCC lead compounds. In this study, structural optimization of the previously identified compound 6f with anti-HCC potential was conducted through diverse substituent modifications on the A- and E-rings, accompanied by systematic structure-activity relationship (SAR) investigations. This effort led to the identification of a new lead compound, Z4, which exhibited potent nanomolar inhibitory activity against four HCC cell lines (IC50 = 0.08 μM for HepG2, 0.16 μM for SK-Hep-1, 0.03 μM for HuH-7, and 0.03 μM for BEL-7404) as well as a doxorubicin-resistant cell line (IC50 = 0.19 μM for SMMC-7721/DOX). Cell-based phenotypic evaluations further demonstrated that Z4 more effectively inhibited proliferation and migration/invasion of BEL-7404 and HuH-7 cells than sorafenib, while inducing cell cycle arrest, mitochondrial dysfunction, reactive oxygen species (ROS) accumulation, and apoptosis. Mechanistically, Z4 exerts its anti-HCC activity primarily through synergistic inhibition of the cAMP-PKA-CREB and PI3K-AKT-mTOR pathways, with only moderate Topo I inhibition observed at high concentrations. In addition, in vivo studies indicated that Z4 possesses acceptable metabolic stability (T1/2 = 8.96 h) and exhibits significantly superior antitumor efficacy compared to sorafenib in a HuH-7 xenograft model. Collectively, this study not only further enriches the SAR of the A-ring of the evodiamine scaffold but also provides a promising lead compound Z4 for anti-HCC drug discovery.

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2026-08-14 | SPP1 promotes the metastasis of liver cancer cells through modulation of the MT1L/vimentin axis.

Tumor metastasis, a hallmark of cancer progression including hepatocellular carcinoma (HCC), is closely linked to poor prognosis. Therefore, strategies to suppress tumor metastasis remain an unresolved challenge for improving patient care. We identified that the oncogenic gene secreted phosphoprotein 1 (SPP1) is highly expressed in HCC tissues. A pseudogene-derived long non-coding RNA, metallothionein 1L (MT1L), was found to be negatively regulated by SPP1. Clinically, MT1L expression was reduced in HCC specimens, and its higher expression correlated positively with favorable prognosis. Notably, MT1L expression was inversely correlated with SPP1 expression in HCC. Mechanistically, SPP1 suppressed MT1L expression through the integrin signaling pathway. Overexpression of MT1L inhibited cell motility and lipid accumulation by repressing vimentin expression. Furthermore, rescue experiments demonstrated that MT1L was functionally involved in SPP1-mediated effects. Collectively, our findings reveal a novel association among the SPP1/MT1L/integrin/vimentin axis in HCC progression, suggesting that targeting this pathway may represent a potential therapeutic approach for HCC.

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2026-07-29 | Harnessing human immune system models to validate NADPH oxidase 1 inhibition as treatment for hepatocellular carcinoma.

NADPH oxidase 1 inhibition (NOX1i) has shown to alter the tumor microenvironment in conventional mouse models for hepatocellular carcinoma (HCC). However, clinical translation is hampered by low translatability of these models. We developed two novel human immune system (HIS) mouse models, co-transplanted with orthotopic human HCC cells, to investigate NOX1i in the context of human HCC and human adaptive (T cell-HIS-HCC) or innate (Myeloid-HIS-HCC) immune responses. Mice received NOX1i or vehicle twice per week for 3 weeks. Results were validated in ex vivo patient-derived precision-cut tumor slices (PCTS). T cell-HIS-HCC mice were mainly reconstituted with human T cells. Interestingly, the expression of cytokines and markers involved in both cancer progression and anti-tumor immunity was significantly lower in tumors of NOX1i-treated mice. In the Myeloid-HIS-HCC model, humanization in livers and tumors was dominated by macrophages. Significantly lower human immune cells were observed in tumors of NOX1i-treated Myeloid-HIS-HCC mice, in line with reduced VCAM1 and ICAM1 expression. NOX1i-treated Myeloid-HIS-HCC mice showed a similar shift in tumor-promoting cytokines and immune checkpoints as NOX1i-treated T cell-HIS-HCC mice. Moreover, gene expression of tumor-associated macrophage, HCC and proliferation markers tended to be lower in tumors of NOX1i-treated Myeloid-HIS-HCC mice. Ex vivo patient-derived PCTS treated with NOX1i also demonstrated lower gene expression of pro-tumorigenic cytokines and tumor-promoting markers. Our data show that NOX1i modulates the tumor-immune microenvironment in human immune system HCC models, and might hold potential in combination therapy to rebalance the dysregulated immune profile in HCC.

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2026-07-28 | Epigenetic Alterations in Hepatocellular Carcinoma: Mechanisms and Biomarkers for Precision Therapy.

Hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality worldwide, is driven by complex interactions between genetic mutations and reversible epigenetic alterations. Among these, aberrant DNA methylation, histone modifications, and dysregulated noncoding RNAs (ncRNAs) play central roles in hepatocarcinogenesis, tumor progression, and therapy resistance. Epigenetic changes not only regulate key oncogenic pathways, including JAK/STAT and RAS, but also contribute to tumor immune evasion and heterogeneity. Unlike genetic mutations, epigenetic alterations are reversible, offering unique opportunities for therapeutic targeting. This review highlights recent advances in understanding the epigenetic landscape of HCC, identifies promising biomarkers for early detection and prognosis, and evaluates emerging epigenetic therapies (including DNMT, HDAC, and BET inhibitors as well as ncRNA-based strategies). Although these therapies have shown tumor-suppressive or treatment-sensitizing effects in preclinical models, their clinical translation remains limited by modest efficacy, small early-phase trials, treatment-related adverse events, and insufficient biomarker-guided patient selection. These insights may support more precise diagnostic and therapeutic strategies for HCC.

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cell therapies

2026-09-06 | Liver transplantation for pediatric liver tumors: a case report of hepatic angiosarcoma with literature review.

Pediatric hepatic angiosarcoma (HAS) is poorly understood. The lack of effective therapies for unresectable pediatric liver tumors creates a clinical imperative, positioning liver transplantation (LT) as a pivotal modality for exploring the roadmap to prolonged survival. We report the first Chinese pediatric case of HAS treated with LT. A 2-year-old boy was admitted to hospital due to abdominal pain and distension. Imaging findings were suggestive of possible malignancy, but initial biopsy yielded a diagnosed infantile hepatic hemangioma (IHH). Following living-donor LT for unresectable disease, explant pathology revealed an angiosarcoma arising within a hemangioma. The patient ultimately died from metastasis 21 months after LT. Our review of pediatric LT for liver tumors over 15 years identified nine pediatric HAS cases, only one of whom was correctly diagnosed pre-LT, with survival ranging from 3 to 66 months. Regarding other tumors, six cases of IHH were reported prior to 2010, without survival data. Recent studies on hepatoblastoma (HB) report a 5-year overall survival (OS) of 80-90%, and the prognosis for hepatocellular carcinoma (HCC) has markedly improved, with a combined 5-year OS of 74%. In the largest reported study, the 5-year OS rates for hepatic epithelioid hemangioendothelioma (HEH) and hepatic undifferentiated embryonal sarcoma (HUES) were 60.6% and 90.0%, respectively. Evidence for biliary tract rhabdomyosarcoma (BT-RMS) and malignant rhabdoid tumor (MRT) of the liver are anecdotal, and no pediatric cases of primary hepatic kaposiform hemangioendothelioma (KHE) treated with LT have been reported. Pediatric HAS is rare and difficult to distinguish from IHH; contrast-enhanced computed tomography/magnetic resonance imaging (CT/MRI) aids differentiation. For suspected malignant transformation, contrast-enhanced ultrasound (CEUS) and ultrasound-guided multi-site biopsy are recommended. No standardized treatment exists for pediatric HAS. Given the poor long-term survival, LT or combined chemotherapy remains exploratory but is the only option for unresectable tumors. The high survival rates of LT for HB and HCC offer a promising blueprint. With advances in surgical techniques and increased living donor availability, pediatric LT deserves more attention.

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2026-08-01 | CPNE1 promotes stemness and confers resistance to GPC3 CAR-T cell therapy in hepatocellular carcinoma via the STAT3-TGF-β signaling pathway.

Hepatocellular carcinoma (HCC) remains a major global health burden with limited effective therapeutic strategies. Although chimeric antigen receptor (CAR) T-cell therapy has shown encouraging potential, its efficacy in HCC is profoundly constrained by the immunosuppressive tumor microenvironment. In this study, we performed integrative analyses of HCC transcriptomic and clinical samples data to identify Copine-1 (CPNE1) as potential oncogenic drivers involved in tumor progression and immune suppression. Using functional and mechanistic assays in vitro with HCC cell line models and in vivo with mouse models, we examined the role of CPNE1 in regulating tumor proliferation, stemness, and its contribution to resistance against GPC3-targeted CAR-T cell therapy. We found that CPNE1 is significantly overexpressed in HCC and correlates with poor patient prognosis. Functional assays revealed that CPNE1 enhances tumor proliferation and stemness by activating the STAT3-transforming growth factor beta (TGF-β) signaling pathway. Moreover, CPNE1-induced secretion of TGF-β promotes T-cell exhaustion, which impairs the efficacy of CAR-T cells. Knockdown of CPNE1 restored CAR-T cell function, enhanced T-cell infiltration into tumors, reduced exhaustion, and improved antitumor efficacy without causing systemic toxicity. Clinically, high CPNE1 expression was associated with lower T-cell infiltration and poor outcomes in HCC patients treated with immune checkpoint inhibitors. These findings identify CPNE1 as a critical regulator of HCC progression and immune suppression, highlighting the CPNE1-STAT3-TGF-β axis as a promising therapeutic target in HCC.

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2026-07-18 | Injectable bioinstructive microfoam for rapid bedside/in vivo programming of CAR-T cells.

While chimeric antigen receptor (CAR) T cell therapies have transformed the treatment of hematological malignancies and are being explored for solid tumors, their widespread use remains limited by high costs, complex manufacturing requirements, long wait times, and unequal access. Here, we describe a methylcellulose-based gene therapy microfoam that enables rapid generation of CAR-T cells for subcutaneous administration within hours of blood collection. Specifically, we demonstrate that colocalization of T cells and vector within the foam promotes efficient CAR gene transfer. Following subcutaneous injection, newly programmed CAR-T cells disperse systemically and mediate regression of distal tumors in mouse xenograft models of lymphoma and hepatocellular carcinoma, with antitumor activity comparable to conventionally manufactured CAR-T cells. The platform operates as a sterile closed system and does not require prolonged cell culture, centralized manufacturing facilities, or cleanroom-based cell production. These findings establish proof of concept for a simplified CAR-T generation strategy that may reduce manufacturing complexity and infrastructure requirements relative to conventional CAR-T therapy while improving the accessibility of cellular immunotherapies.

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2026-06-27 | T-cell receptor-engineered T-cell therapy using a glypican-3-specific TCR derived from a hepatoblastoma vaccine responder for HLA-A2-positive glypican-3-expressing cancers.

Glypican-3 (GPC3) is highly expressed in most hepatocellular carcinomas (HCCs) and hepatoblastoma, shows minimal expression in non-tumor adult tissues, and is also detected in several other malignancies, making it an ideal target for anticancer immunotherapy. We previously demonstrated in clinical trials that GPC3 peptide vaccination can induce durable antitumor immunity in patients with HCC and pediatric hepatoblastoma and established human leukocyte antigen (HLA)-A∗02:01-restricted GPC3-specific cytotoxic T lymphocyte (CTL) clones. In this study, we isolated high-avidity T-cell receptors (TCRs) from CTL clones established from a pediatric hepatoblastoma patient who achieved long-term recurrence-free survival for more than 10 years after surgical resection of pulmonary metastases followed by GPC3 peptide vaccination. Using a retroviral vector incorporating endogenous TCR suppression, these TCR genes were introduced into primary human T cells to generate GPC3-specific TCR-engineered T cells (TCR-T cells). These TCR-T cells exhibited GPC3-specific recognition and significant cytotoxicity against GPC3-positive tumor cells in vitro, while showing minimal activity against GPC3-negative targets. Moreover, GPC3-specific TCR-T cells migrated to tumor sites, resulting in the prevention of tumor engraftment as well as tumor growth suppression and stabilization in xenograft models. GPC3-targeted TCR-T cells derived from CTLs induced by GPC3 peptide vaccination demonstrated potent antitumor activity against HLA-A∗02-positive and GPC3-positive cancers. These findings provide an important rationale for Phase I clinical trials of GPC3-targeted TCR-T cells as a promising therapeutic strategy for GPC3-expressing solid tumors, including HCC and refractory hepatoblastoma.

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2026-05-07 | Allogeneic CRISPR-Engineered CAR-T Cells Drive Potent Antitumor Activity in Solid Tumors.

Chimeric antigen receptor (CAR) T-cell therapy has shown limited efficacy in solid tumors, in part due to variability in autologous T cells derived from heavily pretreated patients with advanced disease. To address these constraints, we developed an off-the-shelf allogeneic CAR-T platform using CRISPR-Cas9-mediated genome editing in T cells from healthy donors to enable targeted CAR insertion at the TRAC locus with concurrent disruption of B2M. Using adeno-associated virus (AAV) delivery, we designed CAR-T cells targeting glypican-2 (GPC2) and glypican-3 (GPC3), emerging antigens expressed in pediatric and adult solid tumors. Genome-edited allogeneic CAR-T cells exhibited potent, antigen-specific cytotoxicity across multiple tumor models. GPC2-directed allogeneic CAR-T cells demonstrated enhanced or comparable activity relative to conventional lentiviral CAR-T cells in neuroblastoma models and mediated tumor regression with prolonged survival in preclinical models. Notably, repeated dosing augmented antitumor efficacy without evidence of toxicity, supporting multi-dose regimens for solid tumors. Similarly, GPC3-targeted allogeneic CAR-T cells based on a single-domain antibody showed robust activity against hepatocellular carcinoma cells in vitro and in vivo. These findings establish a scalable, genome-engineered allogeneic CAR-T strategy with strong therapeutic potential and support the clinical development of off-the-shelf cell therapies for pediatric and adult solid tumors.

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oligonucleotides

2026-05-06 | Personalized immunotherapy in HCC: synthesis, delivery, and clinical progress of mRNA-based vaccines.

Messenger RNA (mRNA)-based vaccines have quickly developed as a unique approach to cancer immunotherapy with specific antigen expression, flexible design, and safety. They are broadly categorized into self-amplifying mRNA (SAM) vaccines and non-replicating mRNA vaccines. SAM vaccines contain viral replicase elements enabling intracellular RNA amplification and strong antigen expression, whereas non-replicating mRNA vaccines encode only the target antigen and rely on direct translation for immunogenicity. Hepatocellular carcinoma (HCC) is a highly aggressive cancer that often exhibits resistance to standard-of-care therapy and appears to benefit from being targeted with mRNA vaccines to produce an anti-tumor immune response. Herein, we review the stepwise approach of vaccine construction of mRNA vaccines, including building a DNA template, in vitro transcription, capping, polyadenylation, and purification of the mRNA, and their delivery as lipid nanoparticles (LNPs), dendritic cells, or naked RNA. In addition, we present a synthesis of progress made through the identification of HCC-specific neoantigens and high-affinity neoantigens (HANs) that activate cytotoxic T cells, correlating with better patient outcomes. Recent preclinical and clinical studies demonstrate the safety and efficacy of mRNA vaccines that encode either tumor-associated or patient-specific neoantigens, often in combination with local therapeutics or immune checkpoint inhibitors. We offer further considerations regarding combinations of mRNA vaccines with strategies including but not limited to adoptive cell therapy, tumor suppressor gene restoration, anti-angiogenesis drugs, and metabolic reprogramming. In many ways, a key consideration is the strategies being developed to overcome the immunosuppressive tumor microenvironment in the liver, and mRNA-induced co-stimulation (e.g., OX40L), TP53 gene editing, and targeting of myeloid-derived suppressor cells. Overall, our review has offered perspectives on the many types of opportunistic strategies being investigated, combining mRNA vaccines to not only prime for anti-tumor immunity or alternate human sources of anti-tumor immunity but also remodel the immunologic landscape that permeates HCC. With numerous ongoing studies and rapid technology advances, mRNA-based immunotherapies are sure to transform how we manage liver cancer.

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2025-11-28 | S···O Conformation Locks Synergistic Alkoxy Chain Engineering of NIR-II Phototheranostic Molecules for Precision Hepatocellular Carcinoma Theranostics.

NIR-II phototheranostics offers a promising strategy for precisely managing deep-seated and refractory tumors. However, the overall optimization of molecular functional properties remains a challenge, and due to the lack of a comprehensive design strategy, there have been limitations in achieving long-wavelength phototherapy, high-fluorescence quantum yield, and photothermal/photodynamic conversion efficiency. This study initially proposes an innovative strategy that involves S···O confirmation locks (SoCLs), synergistic alkoxy chain engineering, and the regulatory influence of the SoCLs on NIR-II S-D-A-D-S-type (shield-donor-acceptor-donor-shield) molecular planarity and successfully optimizes the molecular structure. The resulting IR-BTOG molecules exhibit extended coverage across the NIR-IIa (λex: 1000-1300 nm) and NIR-IIb (λem: 1500-1700 nm) regions, achieving high fluorescence quantum yields and significantly improved photothermal performance. Building on this molecular design, BTOGP-GPC3 nanoparticles (NPs) are further developed by conjugating the hepatocellular carcinoma (HCC)-specific targeting molecule Glypican-3 peptide (GPC3). This conjugation enables precise recognition and diagnosis of HCC. The excellent phototheranostic performance of BTOGP-GPC3 NPs confirms that the SoCLs synergistic alkoxy chain modification strategy markedly enhances the diagnostic performance of the molecule in deep-seated tumors, offering novel opportunities for applying precision phototheranostics in HCC. Moreover, it provides a significant structural design foundation for the future advancement of NIR-II phototheranostic formulations.

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2025-07-24 | Chemoprevention of hepatocellular carcinoma using N-acetylgalactosamine-conjugated siRNAs.

The ability to prevent hepatocellular carcinoma (HCC) in patients with chronic liver disease remains an unmet clinical need. We performed a head-to-head comparison of N-acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA)-mediated inhibition of five genes (CDK1, PD-L1, CTNNB1, SMYD3, ANLN) to prevent cancer in four distinct autochthonous HCC mouse models. siRNA targeting Cdk1 and Anln (siCdk1 and siAnln, respectively) increased overall survival in the CTNNB1/MYC hydrodynamic transfection (HDT) model, in which HCC formation is driven by oncogenes. Both long-term and transient dosing of siCtnnb1 or siAnln prevented cancer development in the NRASG12V/shp53-driven HDT model. siCdk1 and siAnln prevented cancer in a diethylnitrosamine/phenobarbital model, in which tumor formation is driven by mutagenesis and chemical injury. Moreover, siCtnnb1 and siAnln decreased cancer development in a metabolic dysfunction-associated steatohepatitis (MASH) model driven by a Western diet and carbon tetrachloride (CCl4). Given that the use of siAnln was effective in several models, we validated Anln effects using Cre-lox and found that histologic features of MASH and HCC development were independently reduced. This demonstrates that siRNAs are safe and effective in preventing HCC in a large panel of preclinical cancer models, and identifies ANLN as an effective chemoprevention target.

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2024-12-07 | Peptide core spherical nucleic acids circumvent tumor immunosuppression via supplementing methionine for enhanced photodynamic/gene immune/therapy of hepatocellular carcinoma.

Spherical nucleic acids (SNAs) with functional peptide cores are an emerging nanoplatform for synergistic cancer therapy but have been rarely reported. We construct herein the first SNA nanoplatform based on a biodegradable binary peptide backbone of methionine (Met) and cysteine (Cys) for codelivery of a photosensitizer, Chlorin e6 (Ce6) and human liver-specific miR122 for synergistic photodynamic-gene therapy of hepatic cell carcinoma (HCC). Met supplementation by the peptide core improves the infiltration of T cells and enhances the effector function of T cells for turning a "cold" tumor into a "hot" one. The resulting SNA(+) shows the most significant inhibitory effect in a Hepa1-6 HCC primary/distal tumor model, with tumor growth inhibition (TGI) values of 98.5 ± 0.5 % and 99.1 ± 0.4 % for the primary and distant tumors, respectively. This SNA nanoplatform achieves superior high TGI values reported thus far to our knowledge with almost complete eradication for both tumors due to the simultaneous adaptive and innate immunity activation via photodynamic therapy (PDT) induced immunogenic cell death (ICD) and Met supplementation-promoted adaptive immunity, and miR122-enhanced innate immunity. Overall, this study not only develops a reliable synthetic strategy toward peptide-backboned multifunctional SNA nanoplatform, but also reports the modulation of amino acid metabolism for enhanced innate immunity for highly efficient HCC immunotherapy.

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2024-10-09 | Application of XBP1s Decoy Oligodeoxynucleotide Attenuates Cancerous Phenotype in Huh-7 Hepatocellular Carcinoma Cells.

The spliced form of X-box binding protein 1 (XBP1s) is a key transcription factor in the unfolded protein response (UPR), an adaptive mechanism for cell survival. Many studies demonstrated the induced expression of XBP1s in various cancers, including hepatocellular carcinoma (HCC). Such upregulated expression is linked to an enhancement of cell proliferation, migration, and improvement of the survival rate. In this study, we aimed to assess the therapeutic potential of targeting XBP1s, by specific decoy oligodeoxynucleotide (ODN) and evaluated the cancerous phenotypes in Huh-7 cells. In this experimental study, we transfected Huh-7 cells with XBP1s decoy oligonucleotide (ODN). Subsequently, we assess some cellular features, including viability, migration capacity, proliferation potential, and apoptosis. Therefore, various techniques included wound healing test, BrdU, and annexin/PI assays. Additionally, the colony formation capacity was evaluated. The mRNA expression levels of BAX, BCL-2, c-MYC, CCND1, MMP-9, CDH1, and CD133 were quantified by the reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Transfection of Huh-7 cells by XBP1s decoy ODN led to significant down-regulation of c-Myc, CCND1, MMP-9, BCL-2 and CD133 and up-regulation of CDH1 and BAX transcriptional expressions in comparison with the vehicle group. Our results also demonstrated that transfection of XBP1s-decoy reduced HCC cell viability, proliferation, migration capacity as well as colonization ability in comparison with the vehicle group. These findings proposed the potential application of XBP1s-decoy ODN to reduce cancerous phenotypes such as cell proliferation, cell migration and apoptosis induction in the Huh-7 cell line. More experiments on other cell lines and primary cells could validate our results.

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other

2026-08-07 | C1R suppresses hepatocellular carcinoma cell aggressiveness through promoting HIF-1α degradation and modulating cuproptosis-related protein expression.

Hepatocellular carcinoma (HCC) frequently develops in the setting of chronic hepatitis B virus (HBV) infection, yet the molecular events shared by HBV-related liver injury and malignant transformation remain incompletely characterized. Recent studies of cuproptosis indicate that copper overload can disturb mitochondrial metabolic programs in tumor cells. This rationale prompted us to examine copper-responsive alterations across chronic HBV-related liver injury and HCC. TCGA-LIHC and GSE230397 datasets were analyzed to identify shared differentially expressed genes between HCC and chronic HBV infection. Functional enrichment, ssGSEA, WGCNA, and five machine-learning algorithms were used to screen cuproptosis-associated candidate genes. C1R expression, prognosis, immune infiltration, and immune checkpoint correlations were assessed. Experimental validation was then performed in HCC cell lines by manipulating C1R expression and assessing copper modulation, HIF-1α rescue, intracellular localization, protein expression, oxidative stress, cell motility, HIF-1α stability, proteasome inhibition, and ubiquitination. The integrated analysis identified 423 genes with concordant dysregulation in the HBV and HCC datasets. These genes were linked to metal ion response, oxidative stress, and copper-associated biological processes. Cuproptosis-related scores were lower in both HCC tissues and HBV-infected liver samples. Integrative WGCNA and machine-learning analyses identified C1R as the only shared cuproptosis associated candidate gene. C1R was downregulated in HCC and associated with survival, immune infiltration, and immune checkpoint molecules. Functionally, C1R overexpression increased FDX1, DLAT, and DLST expression, elevated ROS accumulation, and suppressed HCC cell migration and invasion, whereas C1R knockdown produced opposite effects. Copper chelation with TTM weakened the effects of C1R overexpression, whereas combined elesclomol and CuCl₂ treatment intensified the C1R-associated changes. C1R also lowered HIF-1α levels by the proteasome-sensitive process accompanied by increased HIF-1α ubiquitination. Restoring HIF-1α expression counteracted the effects of C1R on FDX1, DLAT, DLST, invasion, and migration. C1R is a shared cuproptosis-associated regulator in HBV infection and HCC. The data support a model in which C1R reduces aggressive phenotypes of HCC cells partly through destabilizing HIF-1α and reshaping copper-responsive processes.

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2026-06-15 | KLRB1 gene in tumor immune regulation and disease prognosis: a multidimensional role review.

The CD161 protein encoded by the killer cell lectin-like receptor subfamily B member 1 (KLRB1) gene is a key immunoregulatory molecule, primarily expressed in natural killer (NK) cells and specific T cell subsets, playing a significant role in tumors and various immune-related diseases. With the application of multi-omics big data and single-cell sequencing technologies, the mechanisms by which KLRB1 functions in tumorigenesis, progression, and immune microenvironment regulation are becoming increasingly clear. This paper elucidates the mechanism by which KLRB1 mediates immune activation and immune evasion through the regulation of downstream signaling pathways, its multifaceted roles within the tumor microenvironment (TME), and explores its function in immunotherapy. This article systematically reviews the expression characteristics of KLRB1 in various cancers such as breast cancer, hepatocellular carcinoma, and colorectal cancer, and analyzes the correlation between its expression levels and patient prognosis as well as immune cell infiltration in the TME. Beyond the field of oncology, the important role of KLRB1 in other immune-related diseases such as sepsis, psoriasis, and osteoporosis is also increasingly prominent. In-depth research on KLRB1 will provide new insights for future diagnostic and therapeutic strategies for the aforementioned diseases.

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2026-06-02 | The landscape of pediatric hepatocellular carcinoma and fibrolamellar carcinoma: A report from the Children's Hepatic tumors International Collaboration (CHIC).

Pediatric hepatocellular carcinoma (HCC) and fibrolamellar carcinoma (FLC) have historically been studied on prospective trials in aggregate with hepatoblastoma (HB). It is now recognized that both HCC and FLC have unique histologies, characteristic genomics, and a more aggressive clinical course than HB. It is anticipated that data analyzed from patients treated on previously conducted international trials will inform current and future approaches to the study of these rare diseases. The Children's Hepatic tumors International Collaboration houses data from clinical trials conducted by three global consortia as well as international registries. Data from patients with HCC or FLC who were enrolled on historic trials designed for patients with HB were analyzed for patient demographics, disease characteristics, treatment, and outcomes. The authors identified 236 patients with pediatric HCC or FLC who were enrolled on trials conducted in the United States, Europe, and Japan. As anticipated, HCC and FLC predominantly affected adolescent patients, and outcomes were generally related to extent of disease and resectability. Independent of histology, upfront resection (p = .004) predicted superior survival, likely reflecting the inadequacies of systemic agents to control disease. Outcomes were comparable across studies, with a 5-year survival rate of 36%, independent of chemotherapy received. Survival was equivalent for patients with HCC and FLC after 7-year follow-up. Treatment of pediatric HCC and FLC remains challenging. The current results support risk-stratification methods currently under study prospectively and the independent study of these tumors in the future.

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2026-05-18 | Stromal ACTA2 Counteracts TCDD-Induced Hepatocarcinogenesis via Suppression of the PI3K-AKT-mTOR Pathway.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental pollutant that promotes hepatocellular carcinoma (HCC) through non-genotoxic mechanisms. However, stromal regulatory factors that counteract its tumor-promoting effects remain poorly defined. This study aimed to elucidate the role of actin alpha-2 (ACTA2) in TCDD-associated hepatocarcinogenesis. An integrative strategy combining network toxicology, Mendelian randomization, multi-omics and single-cell analyses, molecular docking and molecular dynamics simulations, along with in vitro experiments, was employed to investigate the functional role of ACTA2. ACTA2 was identified as a stromal-associated factor linked to reduced HCC risk and improved patient survival. Single-cell and multi-omics analyses revealed that ACTA2 is predominantly expressed in hepatic stellate cells and fibroblast-like populations, reflecting tumor microenvironment composition rather than tumor cell-intrinsic expression. Functional enrichment analyses indicated that ACTA2 is associated with extracellular matrix remodeling and PI3K-AKT signaling. Molecular simulations demonstrated stable binding of TCDD to ACTA2 (ΔG_bind ≈ -7.05 kcal/mol), suggesting potential structural perturbation. In vitro experiments showed that TCDD downregulated ACTA2 expression, promoted proliferation of LX-2 and cancer-associated fibroblasts (CAFs), and activated PI3K-AKT-mTOR signaling, whereas ACTA2 overexpression attenuated these effects. ACTA2 acts as a context-dependent stromal regulator that modulates PI3K-AKT-mTOR signaling in TCDD-induced hepatocarcinogenesis. These findings highlight the importance of stromal remodeling in environmental carcinogenesis and suggest ACTA2 as a potential biomarker and therapeutic target in dioxin-associated HCC.

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2026-02-06 | T Cell Exhaustion in Hepatocellular Carcinoma: A Substantial Barrier in Immunotherapy.

Hepatocellular carcinoma (HCC), accounting for over 90% of primary liver cancers, remains a major global challenge for healthcare professionals. While immunotherapy has transformed the landscape of cancer treatment, its success is often limited by immune resistance, particularly through T cell exhaustion which remains a major barrier to effective immune responses in solid tumours, including HCC. As tumours progress, T cells undergo a gradual loss of functionality due to continuous antigen exposure and fail to exert effective anti-tumour responses. During this process, alterations in the epigenome, transcriptome, signalling pathways, and tumour metabolome, in addition to interactions with other cells in the tumour microenvironment, efficiently contribute to T cell exhaustion. Restoring T cell function brings hope for improving therapy outcomes and providing new treatment modalities for HCC patients. In this review, we explore the key cellular and molecular mechanisms driving T cell exhaustion, including the roles of immunosuppressive cells, metabolic stress, and epigenetic alterations focusing on HCC. We also discuss current and emerging strategies aimed at preventing or reversing T cell exhaustion, such as epigenetic modulation, immune checkpoint blockade, metabolic reprogramming, and combination therapies. Understanding these interconnected pathways is critical for designing more effective immunotherapy-based approaches for liver cancer.

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