Hepatocellular carcinoma (HCC) typically develops in chronically inflamed and cirrhotic livers, where malignant hepatocytes are continuously exposed to immune pressure. Although cytotoxic immunity is essential for tumor control, persistent immune activation may paradoxically enable cancer cells to acquire adaptive traits that support disease progression. How this chronic immune pressure contributes to the initiation of metastasis in HCC, however, remains poorly understood.
In a recent 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 HCC. By integrating single-cell RNA sequencing data from non-tumor liver tissues, primary tumors, portal vein tumor thrombi, and distant metastases across three cohorts, the researchers reconstructed malignant hepatocyte trajectories and identified an immune-associated population with a strong metastasis-initiating program.
Analysis of more than 100,000 cells revealed substantial remodeling of the HCC microenvironment, including macrophage enrichment and T-cell depletion within tumors. Notably, portal vein tumor thrombi exhibited cellular compositions resembling distant metastases, suggesting that metastatic competence may emerge early during vascular dissemination. 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 tumors 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 homolog of HLA-E, markedly reduced lung metastases and prolonged survival, establishing a functional role for this molecule in metastatic dissemination.
The researchers next identified interferon-gamma (IFN-γ), a key cytokine released during cytotoxic immune responses, as an upstream regulator of HLA-E. IFN-γ treatment increased HLA-E expression in HCC cells and accelerated lung metastasis in mice. Strikingly, this prometastatic effect disappeared when H2-T23 was silenced, demonstrating that IFN-γ-driven metastatic progression depends on HLA-E.
Mechanistically, IFN-γ activated the JAK–STAT3 pathway, with activated STAT3 directly binding the HLA-E promoter and enhancing its transcription. Pharmacological JAK inhibition or STAT3 knockdown attenuated HLA-E induction, establishing an IFN-γ–JAK–STAT3–HLA-E axis connecting chronic immune stimulation to metastatic adaptation.
Overall, the study reveals that persistent cytotoxic immune pressure can actively shape, rather than merely select for, metastatic traits in HCC. By identifying HLA-E as a mediator of immune-adaptive metastatic evolution, the findings highlight HLA-E and the JAK–STAT3 pathway as potential targets for therapeutic strategies aimed at limiting immune-driven metastasis while improving the effectiveness of immunotherapy.
Reference
Title of Original Paper: Immune pressure drives HLA-E-defined metastatic evolution in hepatocellular carcinoma
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2026.102281
Funding Information:
The National Natural Science Foundation of China (No. 82103206, No. 82173360, No. 82504124)
General Project of Chongqing Natural Science Foundation (China) (No. CSTB2025NSCQ-GPX0367)
Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University (China) (No. kryc-yq-2224)
Open Project (General Project) of the Key Laboratory of Chongqing Municipal Health Commission for Science and Technology Joint Medical Research (China) (No. 2026KFXM047)
Chongqing Science and Health Joint Medical Research Project (China) (No. 2024QNXM053)
Natural Science Foundation of Chongqing Municipality (China) (No. CSTB2024NSCQ-MSX0403)
China Postdoctoral Science Foundation (China) (No. 2022M720606)
Special support for postdoctoral of Chongqing (China) (No. 2022CQBSHTB2064)
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