3D printed biodegradable bilayer films: a promising frontier in liver cancer therapy

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.

Small-molecule-based targeted therapy in liver cancer

Utilizing tumor hypoxia enhances oncolytic viral therapy in liver cancer

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.

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.

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.

Intra-arterial Targeted Islet-specific Expression of Sirt1 Protects β Cells From Streptozotocin-induced Apoptosis in Mice

Introduction Conventional drug delivery systems in cancer therapy face limitations such as poor targeting and adverse side effects. Nanoparticle-based approaches, particularly when integrated with microfluidic technology, have emerged as promising strategies to improve therapeutic precision and outcomes, especially in liver cancer treatment. Areas covered This review discusses recent progress in the use of nanoparticles and polymers for targeted drug delivery, highlighting their ability to encapsulate therapeutic agents and release them at specific sites. The role of microfluidic platforms in drug loading is emphasized, as they enable precise manipulation at micro- and nanoscale levels with minimal sample loss. Literature examining the use of polymer-based nanocarriers, microfluidic-assisted drug encapsulation, and their applications in overcoming tumor growth and liver cancer therapy is analyzed. The article also explores the advantages of microfluidics as a tool for fabricating complex nanosystems for controlled and efficient delivery. Expert opinion Microfluidic-assisted nanoparticle delivery represents a highly promising approach for advancing liver cancer treatment. With its potential to support combination therapies and enable intricate, customizable nanosystems, this platform is likely to shape the future of targeted cancer therapeutics.

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.

Preparation, characterization, and in-vitro studies of doxorubicin-encapsulated silica coated iron oxide nanocomposites on liver cancer cells

The active form of vitamin D(3), 1α,25(OH)(2)D(3) or calcitriol, is known to inhibit the proliferation and invasiveness of many types of cancer cells, including prostate and liver cancer cells. These findings support the use of 1α,25(OH)(2)D(3) for prostate and liver cancer therapy. However, 1α,25(OH)(2)D(3) can cause hypercalcemia, thus, analogs of 1α,25(OH)(2)D(3) that are less calcemic but exhibit potent antiproliferative activity would be attractive as therapeutic agents. We have developed 2α-functional group substituted 19-norvitamin D(3) analogs with and without 14-epimerization. Among them, 2α- and 2β-(3-hydroxypropyl)-1α,25-dihydroxy-19-norvitamin D(3) (MART-10 and -11, respectively) and 14-epi-2α- and 14-epi-2β-(3-hydroxypropyl)-1α,25-dihydroxy-19-norvitamin D(3) (14-epi-MART-10 and 14-epi-MART-11, respectively) were found to be the most promising. In this review, we discuss the synthesis of this unique class of vitamin D analogs, the molecular mechanism of anticancer actions of vitamin D, and the biological evaluation of these analogs for potential application to the prevention and treatment of prostate and liver cancer.

Chimeric antigen receptor (CAR) T cell therapy is a promising approach for cancer treatment; however, its effectiveness in solid tumors is hindered by challenges such as antigen escape due to mutations, heterogenous expression, and immunosuppressive tumor microenvironment. Previously, we developed CAR-T cells targeting glypican-3 (GPC3) for liver cancer using a humanized GPC3-specific monoclonal antibody (hYP7) and human single-domain antibody (HN3). The hYP7 CAR-T cells demonstrate tumor regression in preclinical mouse models and are being used to treat liver cancer patients in a clinical trial at the NIH. In this study, we analyzed clinically-relevant mutations in GPC3 transcripts observed in hepatocellular carcinoma (HCC) patients through RNAseq analysis. Produced the GPC3 variant proteins, and tested whether these mutations may functionally reduce the effectiveness of CAR-T therapies targeting GPC3. We also developed an engineered antibody-gamma/delta TCR (AbTCR) targeting GPC3, incorporating hYP7 and HN3 antibodies against two distinct epitopes on C and N lobes of GPC3, respectively. In an HCC mouse model with low GPC3 antigen density, the GPC3-targeting AbTCR demonstrated superior tumor control and improved overall survival compared to CAR-T cells, attributable to its robust antigen-binding capacity and enhanced tumor infiltrations. Our RNA sequencing analysis revealed a unique set of upregulated genes in tumor-infiltrating AbTCR-T cells compared to CAR-T cells. These genes were associated with T cell functionality and persistence, particularly pathways involving NF-κB and NFAT signaling. The functional analysis data highlight the GPC3-targeting AbTCR as a new potent therapeutic approach for HCC. Citation Format: Dan Li, Tianyuzhou Liang, Hsi-En Tsao, Laura Hutchins, Madilyn Gaydos, Chin-Hsien Tai, Jing Bian, Maggie Cam, Hongbing Zhang, Cheng Liu, Mitchell Ho. A chimeric antibody-based gamma/delta TCR targeting GPC3 overcomes low antigen expression in liver cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3497.

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

As the results of the association between insulin therapy and risk of liver cancer among diabetics have been inconsistent in epidemiological studies, we conducted a meta-analysis to quantify this issue. Data of relevant epidemiological studies were collected by searching articles in PubMed, Web of Science, and Embase till 29 June 2017. Random-effects models were employed to combine study-specific risks. Five cohort studies and nine case-control studies were included in our meta-analysis with 285 008 patients with diabetes mellitus and 4329 liver cancer cases. When we compared insulin-use group with noninsulin use group in patients with diabetes mellitus, we observed a statistically significant association between insulin therapy and liver cancer, with an overall relative risk of 1.90 (95% confidence interval: 1.44-2.50, I=76.1%). We did not find heterogeneity between subgroups stratified by study characteristics and adjusted confounders, except for subgroups related to 'follow-up years' of cohort studies. The combined estimate was robust across sensitivity analysis, and no publication bias was detected. Our results indicated that insulin therapy was associated with elevated incidence of liver cancer among diabetics. Given the high prevalence of diabetes, avoiding excess or unnecessary insulin use to control the blood glucose may offer a potential public health benefit in reducing liver cancer risk. Further studies are warranted to investigate the types, doses, and treatment duration of insulin use in large sample size or cohort of diabetic patients.

Doxorubicin (DOX) is one of the most commonly used drugs in liver cancer. Unfortunately, the traditional chemotherapy with DOX presents many limitations, such as a systematic release of DOX, affecting both tumor tissue and healthy tissue, leading to the apparition of many side effects, multidrug resistance (MDR), and poor water solubility. Furthermore, drug delivery systems' responsiveness has been intensively studied according to the influence of different internal and external stimuli on the efficiency of therapeutic drugs. In this review, we discuss both internal stimuli-responsive drug-delivery systems, such as redox, pH and temperature variation, and external stimuli-responsive drug-delivery systems, such as the application of magnetic, photo-thermal, and electrical stimuli, for the controlled release of Doxorubicin in liver cancer therapy, along with the future perspectives of these smart delivery systems in liver cancer therapy.