Gilded scars: decoding how metabolism and cancer cell-intrinsic features shape immunity in hepatocellular carcinoma

Taranto, D. (2026)

Doctoral Thesis

Hepatocellular carcinoma (HCC) develops within a complex tumour microenvironment shaped by cancer cell genetics, chronic inflammation, and metabolic dysfunction. This thesis investigates how tumour-intrinsic features and immune cell states interact to drive liver cancer initiation, progression, and therapeutic response, with particular emphasis on underexplored myeloid populations. First, it examines the strong biological overlap between metabolic disorders and cancer, highlighting how obesity, type 2 diabetes, and fatty liver disease alter macrophage and T-cell phenotypes in ways that can promote carcinogenesis. It then establishes methodological frameworks for studying HCC in preclinical murine models. Using genetically defined somatic mouse models, this work demonstrates that oncogenic background profoundly influences tumour histopathology, kinetics, and immune composition. In particular, distinct Nras mutations generated either fibrotic, myeloid-rich tumours or steatotic, lymphoid-enriched tumours. Mechanistically, aggressive NrasG12D/PtenKO tumours were shown to secrete GM-CSF through ERK-SP1 signalling, promoting accumulation of pro-inflammatory monocyte-derived myeloid cells that support tumour survival; GM-CSF blockade enhanced tumour necrosis and improved survival, especially when combined with standard-of-care therapy. In a steatotic NrasG12V/PtenKO MASH-HCC model, disease progression was associated with lipid-associated macrophages, exhausted CD8+ T cells, endothelial remodelling, and tertiary lymphoid structures. While targeting lymphoid compartments showed little benefit, TREM2 blockade combined with standard therapy prolonged survival. Collectively, this thesis identifies immune-metabolic and tumour-intrinsic mechanisms that shape HCC and highlights myeloid-targeting strategies as promising therapeutic opportunities.

• Hepatocellular carcinoma (HCC)
• Tumour microenvironment
• Macrophages
• Lipid-associated macrophages
• Immunometabolism
• MASH-associated liver cancer
• Oncogenic signalling
• T cell dysfunction
• GM-CSF signalling
• Myeloid-targeted therapy

• All authors: Taranto, D.
• Supervisor: Akkari, L.; Visser, K.E. de
• Committee: Giera, M.; Wolkers, M.; Kasteren, S.I. van; Verheij, J.
• Qualification: Doctor (dr.)
• Awarding Institution: Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
• Date: 2026-04-07
• DOI: doi:10.60602/1887-4300616