Steatosis‑associated immune alterations and LIGHT‑signaling in hepatic neoplastic disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with higher incidence of hepatic neoplasia and may influence the tumor microenvironment through immune-metabolic mechanisms. In this study, the contribution of intrahepatic natural killer T (NKT) cells and the LIGHT/LTβR/HVEM axis to MASLD severity in patients with primary hepatic cancer (PHC) or colorectal cancer liver metastases (CRCLM) was investigated. Liver biopsies were analyzed and stratified by intrahepatic triglyceride (TG) content into Group I (LIGHT/LTBR/HVEM expression were assessed. Group II showed higher MASLD activity score (MAS), with the greatest score in CRCLM patients. Fibrosis percentage did not differ between groups, although MMP9 and SOX9 gene expression was elevated in Group II, consistent with enhanced extracellular matrix remodeling. The LIGHT/LTBR/HVEM axis gene expression did not differ between groups, but PHC patients from Group II displayed increased LIGHT/LTBR gene expression. Hepatic NKT2 cells were significantly elevated in Group II, more pronounced in CRCLM. In group II, NK-cell abundance inversely correlated with HVEM expression, an association that remained significant after FDR correction. In addition, TP53 mRNA levels were positively associated with expression of components of the LIGHT/LTBR/HVEM axis. Our data reveal associations between MASLD severity, intrahepatic immune-cell composition and the LIGHT/LTBR/HVEM pathway in patients with hepatic neoplastic disease, supporting further investigation of NKT cell subsets and LIGHT signaling as potential markers of the immune-metabolic alterations accompanying steatotic liver disease in this setting.