Background: Metabolic-associated fatty liver disease (MAFLD) has risen as one of the leading etiologies for hepatocellular carcinoma (HCC). Oncogenes have been suggested to be responsible for the high risk of MAFLD-related HCC. We analyzed the impact of the proto-oncogene c-MYC in the development of human and murine MAFLD and MAFLD-associated HCC. Methods: alb-myc^tg mice were studied at baseline conditions and after administration of Western diet (WD) in comparison to WT littermates. c-MYC expression was analyzed in biopsies of patients with MAFLD and MAFLD-associated HCC by immunohistochemistry. Results: Mild obesity, spontaneous hyperlipidaemia, glucose intolerance and insulin resistance were characteristic of 36-week-old alb-myc^tg mice. Middle-aged alb-myc^tg exhibited liver steatosis and increased triglyceride content. Liver injury and inflammation were associated with elevated ALT, an upregulation of ER-stress response and increased ROS production, collagen deposition and compensatory proliferation. At 52 weeks, 20% of transgenic mice developed HCC. WD feeding exacerbated metabolic abnormalities, steatohepatitis, fibrogenesis and tumor prevalence. Therapeutic use of metformin partly attenuated the spontaneous MAFLD phenotype of alb-myc^tg mice. Importantly, upregulation and nuclear localization of c-MYC were characteristic of patients with MAFLD and MAFLD-related HCC. Conclusions: A novel function of c-MYC in MAFLD progression was identified opening new avenues for preventative strategies.

Individuals exhibiting an intermediate alcohol drinking pattern in conjunction with signs of metabolic risk present clinical features of both alcohol‐associated and metabolic‐associated fatty liver diseases. However, such combination remains an unexplored area of great interest, given the increasing number of patients affected. In the present study, we aimed to develop a preclinical DUAL (alcohol‐associated liver disease plus metabolic‐associated fatty liver disease) model in mice. C57BL/6 mice received 10% vol/vol alcohol in sweetened drinking water in combination with a Western diet for 10, 23, and 52 weeks (DUAL model). Animals fed with DUAL diet elicited a significant increase in body mass index accompanied by a pronounced hypertrophy of adipocytes, hypercholesterolemia, and hyperglycemia. Significant liver damage was characterized by elevated plasma alanine aminotransferase and lactate dehydrogenase levels, extensive hepatomegaly, hepatocyte enlargement, ballooning, steatosis, hepatic cell death, and compensatory proliferation. Notably, DUAL animals developed lobular inflammation and advanced hepatic fibrosis. Sequentially, bridging cirrhotic changes were frequently observed after 12 months. Bulk RNA‐sequencing analysis indicated that dysregulated molecular pathways in DUAL mice were similar to those of patients with steatohepatitis. Conclusion: Our DUAL model is characterized by obesity, glucose intolerance, liver damage, prominent steatohepatitis and fibrosis, as well as inflammation and fibrosis in white adipose tissue. Altogether, the DUAL model mimics all histological, metabolic, and transcriptomic gene signatures of human advanced steatohepatitis, and therefore serves as a preclinical tool for the development of therapeutic targets.

Chimeric antigen receptor (CAR)-T cell therapy has proven to be a powerful treatment for hematological malignancies. The situation is very different in the case of solid tumors, for which no CAR-T-based therapy has yet been approved. There are many factors contributing to the absence of response in solid tumors to CAR-T cells, such as the immunosuppressive tumor microenvironment (TME), T cell exhaustion, or the lack of suitable antigen targets, which should have a stable and specific expression on tumor cells. Strategies being developed to improve CAR-T-based therapy for solid tumors include the use of new-generation CARs such as TRUCKs or bi-specific CARs, the combination of CAR therapy with chemo- or radiotherapy, the use of checkpoint inhibitors, and the use of oncolytic viruses. Furthermore, despite the scarcity of targets, a growing number of phase I/II clinical trials are exploring new solid-tumor-associated antigens. Most of these antigens are of a protein nature; however, there is a clear potential in identifying carbohydrate-type antigens associated with tumors, or carbohydrate and proteoglycan antigens that emerge because of aberrant glycosylations occurring in the context of tumor transformation.

The mesoporous silicon microparticles (MSMPs) are excellent vehicles for releasing molecules inside the cell. The aim of this work was to use MSMPs to deliver viral specific MHC class I restricted epitopes into human antigen presenting cells (monocyte derived dendritic cells, MDDCs) to facilitate their capture, processing, and presentation to CD8+ (cytotoxic) T lymphocytes. We show for the first time that MSMPs vehiculation of antigenic peptides enhances their MHC class I presentation by human MDDCs to CD8 T lymphocytes.