Patient-derived models of liver cancer to inform therapeutic decision: recent updates

Primary liver cancer remains a global health challenge due to rising incidence, limited curative options, and poor overall survival. Poor outcomes stem from tumor heterogeneity, limited efficacy of current therapies, and co-morbid chronic liver disease. Despite recent advances in immunotherapy and combination treatments, response rates remain low, and predictive biomarkers are lacking. As a result, there is an urgent need for preclinical models that capture the molecular, cellular, and immune landscape of primary liver cancer. This review discusses the strengths and limitations of patient-derived models of liver cancer, including two-dimensional patient-derived cell lines (PDCL), three-dimensional (3-D) patient-derived tumor organoids (PDTOs), and patient-derived xenografts (PDXs). While PDCLs and PDTOs enable high throughput studies, they lack a representative tumor microenvironment. PDXs, including PDXs in animals with humanized immune systems, may more effectively mimic tumor-environment interactions but are costly, complex, and still contain mouse stromal cells. Ex vivo tissue culture preserves tissue structure and cell-cell interactions in an immunocompetent environment; however, short duration of viable culture limits broader application. Continued innovation in the development of multi-cellular 3-D culture systems and in vivo humanization strategies will play a critical role in enabling the development of more personalized and effective therapies for primary liver cancer.