Review Article

Advances in basic and translational research on the heterogeneity and metastatic mechanisms of primary liver cancer

¹ Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, PR China
² International Cancer Institute, State Key Laboratory of Molecular Oncology, Peking University, Beijing, 100191, PR China
³ St Peters Lutheran college Indooroopilly School, 66 Harts Road Indooroopilly, 4068, Brisbane, QLD, Australia
⁴ Translational Cancer Research Center, Peking University First Hospital, Beijing, 100034, PR China

^* Corresponding author: zhangning@bjmu.edu.cn

Received: 24 June 2025
Accepted: 5 July 2025

Abstract

Primary liver cancer remains one of the most prevalent malignancies worldwide. Despite recent progress in targeted therapies and immunotherapies, clinical benefits are limited to a small subset of patients. Drug resistance, metastasis, and disease recurrence continue to impede therapeutic success. Moreover, the heterogeneity of tumor cells and the immune microenvironment has emerged as a major barrier to effective treatment. This review systematically summarizes advances from our laboratory in elucidating the molecular and cellular heterogeneity of primary liver cancer, encompassing tumor genomic evolution, phenotypic diversity, and immune ecosystem complexity. We further highlight the application of patient-derived organoid models for pharmacogenomic profiling, biomarker discovery, and therapeutic development. Finally, we discuss future directions integrating single-cell multi-omics, organoid-based functional screening, and large-scale clinical cohort studies to advance precision medicine in liver cancer. Collectively, these efforts provide critical insights into the biology of primary liver cancer and inform new strategies to improve patient outcomes.