Bioengineered 3D Liver Tumor Systems and Patient-Derived Organoids: A New Paradigm in Precision Oncology

Hepatocellular carcinoma, the most prevalent primary liver malignancy, remains a global health burden characterized by late-stage diagnosis, high recurrence rates, and limited systemic therapeutic options. Conventional 2-dimensional cell cultures and animal models fail to recapitulate the architectural complexity, cellular heterogeneity, and dynamic tumor microenvironment (TME) of human liver tumors, severely limiting their translational utility. Three-dimensional (3D) liver tumor models, particularly patient-derived organoids, have emerged as transformative platforms that preserve the structural, cellular, and molecular fidelity of primary tumors, addressing a critical unmet clinical need for more predictive preclinical systems. This review critically examines the development, characterization, and applications of 3D liver tumor models, with structured discussion of organoid biology, biomimetic TME engineering, drug screening, and translational limitations. We further evaluate the convergence of 3D systems with artificial intelligence, bioprinting, and microfluidics. Critically, we address the marked yet underappreciated barriers to clinical translation including high cost, prolonged culture timelines, technical complexity, and the absence of standardized protocols and propose actionable directions toward standardization using frameworks such as the Minimum Information about Organoid Research. Finally, we outline the next key technical challenges that must be solved, including the establishment of liver tumor organoid biobanks and the design of organoid-guided companion diagnostic clinical trials, to bridge the gap between bench discovery and bedside application.