55 Hepatocellular carcinoma typically develops in chronically inflamed and cirrhotic livers, where malignant hepatocytes are exposed to continuous immune pressure. Although cytotoxic immunity is essential for tumour control, persistent immune activation may allow cancer cells to acquire adaptive traits that support disease progression. How this chronic immune pressure contributes to the initiation of metastasis in hepatocellular carcinoma has remained poorly understood. In a study published in Genes & Diseases, researchers from Chongqing Medical University and The Third Military Medical University investigated how sustained immune pressure shapes metastatic evolution in hepatocellular carcinoma. By integrating single-cell RNA sequencing data from non-tumour liver tissue, primary tumours, portal vein tumour thrombi, and distant metastases across three cohorts, the researchers reconstructed malignant hepatocyte trajectories and identified an immune-associated population with a strong metastasis-initiating programme. Analysis of more than 100,000 cells revealed substantial remodelling of the hepatocellular carcinoma microenvironment, including macrophage enrichment and T-cell depletion within tumours. Portal vein tumour thrombi, a common and clinically significant feature of advanced hepatocellular carcinoma, displayed cellular compositions resembling those of distant metastases. This suggests that metastatic competence may emerge early during vascular dissemination and that these thrombi may already harbour cells primed for distant spread. Further trajectory analysis identified an immune-related malignant hepatocyte population as the predominant source of metastasis-initiating seed cells. Among these cells, HLA-E, a non-classical major histocompatibility complex class Ib molecule, emerged as a defining marker of metastatic potential. HLA-E expression correlated strongly with metastasis-initiating scores and was elevated in tumours from patients with distant metastases. High HLA-E expression was also associated with poorer overall survival. In orthotopic mouse models, silencing H2-T23, the murine homologue of HLA-E, markedly reduced lung metastases and prolonged survival, providing functional evidence of the molecule’s role in metastatic dissemination. The researchers next identified interferon-gamma, a key cytokine released during cytotoxic immune responses, as an upstream regulator of HLA-E. Treating hepatocellular carcinoma cells with interferon-gamma increased HLA-E expression and accelerated lung metastasis in mice. However, this prometastatic effect disappeared when H2-T23 was silenced, indicating that interferon-gamma-driven metastatic progression depends on HLA-E. The finding is notable because interferon-gamma is normally associated with antitumour activity, yet it may paradoxically promote tumour dissemination when it induces HLA-E. Mechanistically, interferon-gamma activated the JAK-STAT3 pathway, with activated STAT3 binding directly to the HLA-E promoter and enhancing its transcription. Pharmacological JAK inhibition or STAT3 knockdown reduced HLA-E induction, establishing an interferon-gamma → JAK-STAT3 → HLA-E axis that connects chronic immune stimulation with metastatic adaptation. Overall, the study suggests that persistent cytotoxic immune pressure can actively shape, rather than merely select for, metastatic traits in hepatocellular carcinoma. The disease remains a leading cause of cancer-related mortality worldwide and often develops against a background of chronic liver disease caused by viral hepatitis, alcohol, or metabolic factors. Many patients are diagnosed at an advanced stage, when vascular invasion or distant spread may already be present. Understanding the interplay between ongoing immune surveillance and tumour evolution is therefore critical. The findings add to growing evidence that tumour cells can co-opt elements of the immune response to support disease progression. By identifying HLA-E as a mediator of this immune-adaptive metastatic evolution, the study highlights HLA-E and the JAK-STAT3 pathway as potential targets for therapeutic strategies designed to limit immune-driven metastasis while preserving the effectiveness of antitumour immunity. Targeting this axis could potentially restrain metastatic adaptation without completely compromising protective immune responses. However, further clinical research is needed to determine whether HLA-E expression or JAK-STAT3 activity could serve as biomarkers of metastatic risk or therapeutic targets in combination with existing immunotherapies. Such approaches could ultimately help address one of the most challenging aspects of hepatocellular carcinoma.