Niche-Specific Reprogramming of Macrophages Reveals Myeloid Cell-Centric Targets During Pro-Senescence Therapy in Liver Cancer

Liver cancer is a generic term referring to several cancer types arising from the liver. Every year, liver cancer causes lots of deaths and other burdens to the people all over the world. Though the techniques in the diagnosis and therapy of liver cancer have undergone significant advances, the current status of treating liver cancer is not satisfactory enough. The improvement of techniques for the prognosis of liver cancer patients will be a great supplement for the treatment of liver cancer. Cuproptosis is a newly identified regulatory cell death type, which may have a close connection to liver cancer pathology. Here, we developed a prognostic model for liver cancer based on the cuproptosis-related mRNAs and lncRNAs. This model can not only effectively predict the potential survival of liver cancer patients, but also be applied to evaluate the infiltration of immune cell, tumor mutation burden, and sensitivity to anti-tumor drugs in liver cancer. In addition, this model has been successfully validated in lots of liver cancer patients’ data. In summary, we wish this model can become a helpful tool for clinical use in the therapy of liver cancer.

Liver cancer is one of the most prevalent malignant tumors worldwide. According to the staging criteria of Barcelona Clinic Liver Cancer, clinical guidelines provide tutorials to clinical management of liver cancer at their individual stages. However, most patients diagnosed with liver cancer are at advanced stage, thereby, many researchers conduct investigations on targeted therapy, aiming to improve the overall survival of these patients. To date, small molecule-based targeted therapies are highly recommended (fist-line: Sorafenib and Lenvatinib; second-line: Regorafenib and Cabozantinib) by current clinical guidelines of American Society of Clinical Oncology, European Society for Medical Oncology, and National Comprehensive Cancer Network. Herein, we summarize the small molecule-based targeted therapies in liver cancer, including the approved and preclinical therapies as well as the therapies under clinical trials, and introduce their history of discovery, clinical trials, indications, and molecular mechanisms. For drug resistance, the revealed mechanisms of action and the combination therapies are also discussed. In fact, the known small molecule-based therapies still have limited clinical benefits to liver cancer patients. Therefore, we analyze the current status and give our ideas for the urgent issues and future directions in this field, suggesting the clues for novel techniques in liver cancer treatment.

Utilizing tumor hypoxia enhances oncolytic viral therapy in liver cancer

Liver cancer is the third leading cause of cancer-related deaths globally. The number of liver cancers diagnosed in the world is increasing at an alarming rate. It is of great significance to find the new targets of the tumor cells and specific medicine. This research investigated the expression of interleukin-13 receptor alpha2 (IL-13Ralpha2) in different liver cancer cell lines and liver cancer tissues, and assessed the cytotoxin DT389-hIL13-13E13K (IL-13 and diphtheria toxin fusion protein) targeted killing effect on liver cancer cells. Based on study above, we further analyzed the function of IL-13Ralpha2 on the targeted liver cancer therapy. The results will provide a novel strategy and an alternative way for liver cancer therapy. The expression of IL-13Ralpha2 in different liver cancer cell lines and tissues were analyzed by RT-PCR and immunohistochemistry. Cytotoxicity assay of DT389-hIL13-13E13K was performed in eight different concentrations in liver cancer cell lines in vitro. At the same time, siRNA-mediated knockdown was introduced to assess the role of IL-13Ralpha2 in liver cancer therapy. Two out of four tested liver cancer cell lines and 27 out of 33 (81.82%) liver tissues expressed the IL-13Ralpha2. The fusion protein DT(389)-hIL13-13E13K showed a moderate cytotoxicity to the cancer cell line BEL-7402 in vitro, which 50% inhibition (IC(50)) concentration occurred at 1.4 x 10(-5 )M. Besides, the sensitivity to fusion protein DT(389)-hIL13-13E13K was decreased in siRNA-transfected liver cells compared with control ones. These results suggest that IL-13Ralpha2 chain is a specific target for IL-13-directed fusion protein. We reported the expression of IL-13Ralpha2 in liver cancer cell lines and tissues as well as investigated the cytotoxin (DT389-hIL13-13E13K) targeted killing efficiency of liver cancer cells and potential role of IL-13Ralpha2 in the cancer treatment.

Surgery is the main treatment for liver cancer in clinic owing to its low sensitivity to chemotherapy and radiotherapy, but this results in high mortality, recurrence, and metastasis rates. It is a feasible strategy to construct tumor microenvironments activated by nanotheranostics agents for the diagnosis and therapy of liver cancer. This study reports on a nanotheranostic agent (MONs@PDA-ICG) with manganese oxide nanoflowers (MONs) as core and polydopamine (PDA) as shell loading, with ICG as a photosensitizer and photothermal agent. MONs@PDA-ICG can not only produce ROS to kill cancer cells but also exhibit good photothermal performance for photothermal therapy (PTT). Importantly, O2 generated by MONs decomposition can relieve the tumor hypoxia and further enhance the treatment effects of photodynamic therapy (PDT). In addition, the released Mn2+ ions make MONs@PDA-ICG serve as tumor microenvironments responsive to MRI contrast for highly sensitive and specific liver cancer diagnosis.

Hepatocellular carcinoma (HCC) accounts for 70% of liver cancer diagnoses globally and is estimated to be the sixth leading cause of cancer-related deaths. Current pre-clinical models inadequately mimic the complex tumor microenvironment (TME), whose cellular and extracellular components can enhance or suppressed the efficacy of existing therapeutics. Understanding this ecosystem is critical to developing therapy approaches that can improve the odds of survival in HCC patients. We developed an innovative in vitro vascularized liver tumor model in a microfluidic platform that mimics a hypoxic tumor core, tumorigenic ECM niche, and perfusable vascular networks. Liver tumor spheroids were surrounded by stromal cells that self-assemble to form a perfusable microvasculature network with physiologically relevant permeability. This model was used to evaluate the influence of vascular networks on drug and adoptive cell therapy. Compared to non-vascularized models, intravascularly administered Sorafenib showed significant disruption of vessels and heterogeneous tumor responses in HepG2 and Hep3b tumor spheroids. The presence of vasculature significantly impeded the infiltration of engineered T-cells. Interestingly, despite poor infiltration, their cytotoxic effector functions remain unaffected. Furthermore, functional profiling of T-cells within the TME revealed reduced levels of exhaustion. Cytokine analysis and spatial transcriptomic profiling revealed that vascularized tumors secrete proinflammatory signals that could enhance or maintain antitumor responses of T-cells. In summary, our platform effectively mimics critical aspects of the in vivo TME, improving the predictability of treatment outcomes and offering promising avenues for personalized medicine. Citation Format: Jyothsna Vasudevan, Damien Tan, Ragavi Vijayakumar, Jose Antonio Reales-Calderon, Maxine S Y Lam, Jin Rong Ow, Joey Aw, Anthony Tan Tanoto, Antonio Bertoletti, Giulia Adriani and Andrea Pavesi. Harnessing vascularized in vitro tumor models to unveil microenvironmental impact on drug and cell therapy in liver cancer [abstract]. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85(15_Suppl):Abstract nr P41.

Chimeric antigen receptor-engineered T-cell therapy for liver cancer

Liver cancer is one of the most common malignant tumors in the world and metastasis is the leading cause of death associated with liver cancer. Hypoxia is a common feature of solid tumors and enhances malignant character of cancer cells. However, the exact mechanisms involved in hypoxia-driven liver cancer progression and metastasis have not been well clarified so far. The aim of this study was to investigate the contribution of long non-coding RNA (lncRNA) in hypoxia promoting liver cancer progression. We screened and revealed LINC00839 as a novel hypoxia-responsive lncRNA in liver cancer. LINC00839 expression was up-regulated in liver cancer tissues and cell lines, and the patients with high LINC00839 expression had shortened overall survival. LINC00839 further overexpressed under hypoxia and promoted liver cancer cell proliferation, migration, and invasion. Mechanistically, LINC00839 bound multiple proteins that were primarily associated with the metabolism and RNA transport, and positively regulated the expression of Formin-like protein 2 (FMNL2). LINC00839 could promote hypoxia-mediated liver cancer progression, suggesting it may be a clinically valuable biomarker and serve as a molecular target for the diagnosis, prognosis, and therapy of liver cancer.

ObjectiveEvaluate the therapeutic efficacy and safety of Traditional Chinese Medicine (TCM) in patients with primary liver cancer (PLC) receiving targeted therapy.MethodsWe conducted a comprehensive search of databases. The search scope covered the period from the establishment of the databases to April 2025. We included 49 randomized controlled trials (RCTs) evaluating targeted therapy for primary liver cancer with TCM. Efficacy and safety outcomes were assessed using risk ratios (RR), standardized mean differences (SMD), and their 95% confidence intervals (CI).ResultsTargeted therapy for liver cancer patients who received TCM treatment showed improvements in objective response rate (ORR) (RR, 1.49 [1.33-1.66], P < 0.0001), disease control rate (DCR) (RR, 1.32 [1.25,1.40], P < 0.0001), the 1-year survival (RR, 1.50 [1.20,1.88]; P = 0.0004) and Karnofsky Performance Status (KPS) (SMD, 1.34 [0.86,1.81]; P < 0.0001), and can reduce the incidence of adverse events, as well as to some extent decrease the production of tumor markers and related inflammatory factors.ConclusionTCM enhances the efficacy and safety of targeted therapy in PLC, offering superior clinical outcomes with fewer adverse effects. These findings support its potential integration into standard treatment protocols.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD420251055085.

Liver cancer is currently the fifth most common solid tumor worldwide, causing almost 7000 deaths every year. Among primary liver cancers, hepatocellular carcinoma (HCC) represents the major histological subtype, accounting for 70% to 85% of the total liver cancer burden. To date, the major etiologies and risk factors for liver cancer development are well-defined. Due to the progress in clinical and biological fields, the primary carcinogenetic steps and molecular mechanisms have been elucidated in recent decades. The interventions for liver cancer patients vary depending on the stages. Surgical resection remains the most effective method for liver cancer patients of early stage. For patients of advanced stages, palliative therapies such as percutaneous ethanol injection, radiofrequency ablation, microwave ablation, transarterial chemoembolization (TACE), selective internal radiation therapy (SIRT), and sorafenib are recommended treatment choices for unresectable liver cancers. Despite the advances in diagnostic and therapeutic measures, the prognosis of liver cancer is not satisfying, with the 5-year survival rate being less than 12%. So the discovery of new interventions is still in demand. Recently, much attention has been paid to exploring new molecular mechanisms that might be involved in liver cancer biological behaviors. We believe further study of novel targets and small molecular interventions would be helpful to improve the prognosis of liver cancer. In this current issue, we focus on recent advances in the field of novel targets and small molecular interventions for liver cancer which might help reveal the possible mechanism of tumorigenesis, progression, metastasis, and recurrence of liver cancer and contribute to emerging therapeutics for liver cancer. We present nine articles on novel targets and small molecular interventions for liver cancer of which six investigate the targets and mechanisms for hepatocarcinogenesis, progression, metastasis, recurrence, and HCC drug resistance, two introduce novel agents for HCC treatments, and one makes a comprehensive review on the novel molecular targets for future therapies of HCC. The paper titled “Reexpression of let-7g microRNA inhibits the proliferation and migration via K-Ras/HMGA2/snail axis in hepatocellular carcinoma” by K. Chen et al. found that reexpression of let-7g inhibited the proliferation, migration, and invasion of HCC, and low expression of let-7g was significantly associated with poorer overall survival. The work by H. Xiao et al. investigated BAG3 and HIF-1α expression in HCC tissues and analyzed the association between BAG3 and HIF-1α coexpression and prognosis following liver transplantation. They found that expression level of BAG3 and HIF-1α was efficient prognostic parameters in patients with HCC after liver transplantation. The work by Z. Wang et al. analyzed the association between two common polymorphisms (miR-146a G>C and miR-196a2 C>T) and risk of HCC by meta-analysis. MiR-146a G>C and miR-196a2 C>T were associated with decreased HCC susceptibility, especially in Asian population. The work by Y.-X. Liu et al. analyzed the role of microRNA-24 in HCC related to aflatoxin B1 and revealed miR-24 was upregulated in HCC tumor tissues. MicroRNA-24 overexpression modified the recurrence-free survival and overall survival of HCC patients. The joint effects between miR-24 and AFB1 exposure on HCC prognosis were also observed. The work by W. Chen et al. investigated tumor microenvironment on HCC cell's reaction to sorafenib. The oral multi-tyrosine kinase inhibitor sorafenib is the only approved systemic therapy for HCC patients in BCLC stage C with significant survival benefit. In this paper, Chen revealed that hepatic stellate cell- (HSC-) LX2 coculture induced sorafenib resistance in Huh7 through HGF/c-Met/Akt pathway and Jak2/Stat3 pathway which gave support to the theory that tumor microenvironment confers drug resistance to kinase inhibitors. C. Peng et al. studied the function of tumor suppressor ZDHHC2 in HCC. Loss of heterozygosity on ZDHHC2 was associated with early metastatic recurrence following liver transplantation. Restoration of ZDHHC2 inhibited HCC proliferation, migration, and invasion. In the work by Z. Wang et al., baicalein was found to exhibit prominent anti-HCC activity. This flavonoid induces apoptosis and protective autophagy via ER stress. Combination of baicalein and autophagy inhibitors may represent a promising therapy against HCC. The work titled “Dehydroabietic acid derivative QC2 induces oncosis in hepatocellular carcinoma cells” by G. Zhang et al. investigated the inhibitory effect of a new dehydroabietic acid derivative QC2 on HCC. They found that QC2 induced HCC cell death by oncosis through activating oncosis related protein calpain. The review article “Hepatocellular carcinoma: novel molecular targets in carcinogenesis for future therapies” by G. Bertino et al. made a general review on novel molecular targets in carcinogenesis for HCC. In summary, development of novel systemic therapies for advanced liver cancer, including drugs, small molecular agents, and gene therapies, is of paramount importance. This special issue presents several intriguing achievements in the area of novel targets and small molecular interventions which we believe could be utilized in liver cancer therapy in the future.

Liver cancer is an extraordinarily heterogeneous malignancy with relatively high mortality and increasing incidence rate among the so far identified cancers. Improvements in liver cancer therapy have been made in the past decades, but therapeutics against liver cancer are still limited. Traditional Mongolian Medicine, formed and developed by the Mongolian people to maintain health in the medical practice of fighting against diseases, has been recognized as one of the key components of the world healthcare system. Traditional Mongolian Medicine has been used to treat various malignancies, including liver cancer, for a long time in Asia and its advantages have become more and more apparent. Herein, this review made a comprehensive summary of Traditional Mongolian Medicine, including the ideas in the liver cancer treatment, sources of medicines or prescriptions, traditional applications, modern pharmacological research, chemical structure and mechanisms of several monomer compounds isolated from Traditional Mongolian Medicine, with a view to finding promising drugs against liver cancer and expanding the clinical application of Traditional Mongolian Medicine in liver cancer therapy.

Liver cancer is a major malignant tumor, which seriously threatens human health and increases the economic burden on patients. At present, gene therapy has been comprehensively studied as an excellent therapeutic measure in liver cancer treatment. Oncolytic virus (OV) is a kind of virus that can specifically infect and kill tumor cells. After being modified by genetic engineering, the specificity of OV infection to tumor cells is increased, and its influence on normal cells is reduced. To date, OV has shown its effectiveness and safety in experimental and clinical studies on a variety of tumors. Thus, this review primarily introduces the current status of different genetically engineered OVs used in gene therapy for liver cancer, focuses on the application of OVs and different target genes for current liver cancer therapy, and identifies the problems encountered in OVs-based combination therapy and the corresponding solutions, which will provide new insights into the treatment of liver cancer.

MicroRNAs (miRNAs) play critical roles in the growth, metastasis and therapeutic resistance of liver cancer. Accumulating evidence suggests that miR-498 is aberrantly expressed in several human malignancies. However, the role and underlying mechanism of miR-498 in liver cancer remain unclear. In the present study, we investigated the potential roles and clinical value of miR-498 in liver cancer. We found that the miR-498 expression level was significantly lower in liver cancer patient tissues than that in healthy control tissues. The expression of miR-498 was also decreased in liver cancer cell lines compared to that noted in a normal human normal liver cell line. miR-498 overexpression markedly inhibited liver cancer cell proliferation, migration and invasion. miR-498 overexpression induced cell cycle arrest and apoptosis while it suppressed epithelial-mesenchymal transition (EMT) in liver cancer cells. Bioinformatic analysis and luciferase reporter assay further identified zinc finger E-box binding homeobox 2 (ZEB2) as a novel target of miR-498. Furthermore, ZEB2 knockdown recapitulated the inhibitory effects of miR-498 overexpression in liver cancer cells. ZEB2 overexpression rescued the inhibition of liver cancer cell proliferation, migration, and invasion by miR-498, indicating that ZEB2 acts as a downstream effector of miR-498 in liver cancer cells. Thus, we demonstrated that miR-498 suppresses the growth and metastasis of liver cancer cells, partly at least, by directly targeting ZEB2, suggesting that miR-498 may serve as a potential biomarker for the diagnosis and therapy of liver cancer.

Chapter 14 - Glutamine metabolism in liver cancer: role in progression and potential therapeutic targeting

Liver cancer, including hepatocellular carcinoma (HCC) as the major type, is a serious malignant tumor with high morbidity and mortality worldwide. Long noncoding RNAs (lncRNAs) play an essential role in the pathogenesis and development of liver cancer, as they can cooperate with and modulate other molecules, particularly RNA binding proteins (RBPs), to perform regulatory functions. Conversely, RBPs also deeply influence the functional manner of lncRNAs in cancer cells. Thus, it is critical to decipher how lncRNAs and RBPs interact with each other, affect the expression, localization, structure, modification, or function of their partners, and induce the following biological programs. In the present review, the interactions between lncRNAs and RBPs identified over the past years are examined, and their modes of cooperation and downstream effects on liver cancer progression are explored. Briefly, lncRNA-RBP pairs were classified into different categories according to their mechanisms of interaction and their influence on liver cancer development, including how their interactions affect one another, how they cooperate to regulate targets, and the resulting functional outcomes on liver cancer. In addition, the current state-of-the-art databases and technologies used to identify potential interactions between lncRNAs and RBPs were also emphasized, including crosslinking and immunoprecipitation, RNA immunoprecipitation, RNA pull-down and mass spectrometry. In summary, the present review systematically summarized the regulatory functions of lncRNA-RBP pairs in liver cancer, which suggests the potential to harness RNA-based therapeutics as an alternative treatment modality for liver cancer.