TERT drives liver tumorigenesis and immune reprogramming independently of telomere elongation

We generated two mouse models, p21⁺/Tert and p21⁺/TertCi, that express either telomerase reverse transcriptase (TERT) or its catalytically inactive form under the control of the p21 promoter, establishing a feedback loop that restricts telomerase expression to p21-positive cells. By 18–20 months of age, approximately 15% of mice from both genotypes developed liver tumors with histopathological features resembling human hepatocellular carcinoma (HCC). Whole-exome sequencing revealed activating mutations in Ctnnb1 in p21⁺/Tert tumors, and activating HrasGln61Lys mutations in p21⁺/TertCi tumors, associated with elevated C>A transversions as well as recurrent PP1 subunit mutations in multiple tumors. Despite distinct point mutations, both models exhibited chromosomal alterations recurrent in human HCC. β-catenin–activated tumors displayed gene expression signatures characteristic of human HCC, as well as SLC1A5 overexpression, whereas MAPK-mutated tumors showed transcriptional profiles consistent with MAPK/ERK pathway activation. Both genotypes demonstrated upregulation of glycolytic enzymes and downregulation of gluconeogenic enzymes such as FBP1, but overexpressed distinct NRF2 targets. Spatial architecture of the tumors using the Hyperion™ Imaging System revealed reduced HNF4A-positive hepatocytes in all tumors, independent of Hnf4a transcriptional changes, and markedly decreased immune cell infiltration in β-catenin–activated tumors. Together, these results uncover unanticipated roles for TERT beyond telomere elongation and identify molecular and metabolic biomarkers predictive of immunotherapy response in HCC.