Patient-derived tumor organoid models for functional precision oncology in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is characterized by marked intertumoral and intratumoral heterogeneity, which contributes to highly variable responses to systemic therapy and limits the clinical utility of current biomarker-driven precision strategies. Growing evidence suggests that static molecular profiling alone cannot fully capture the functional determinants of therapeutic response, particularly for immune checkpoint-based treatment. In this review, we discuss the concept of functional precision oncology in HCC and provide a structured framework for positioning patient-derived tumor models across the translational spectrum. We compare long-term expandable patient-derived organoids (PDOs), short-term patient-derived organotypic tumor spheroids (PDOTS), and patient-derived tumor fragments (PDTFs), emphasizing their distinct biological scopes and translational roles. Whereas conventional PDOs support scalable assessment of tumor cell-intrinsic drug sensitivity, organotypic platforms preserve endogenous immune and stromal components and therefore permit direct ex vivo interrogation of immunotherapy responses. We further discuss how functional drug-response data generated from these models can serve as phenotypic ground truth for interpreting multi-omics data and informing computational and AI-assisted predictive frameworks. Finally, we outline key challenges related to standardization, scalability, and clinical integration, and propose a roadmap for incorporating patient-derived functional tumor models into precision therapy development for HCC.

Keywords

Hepatocellular carcinoma / patient-derived organoids / functional precision oncology / tumor microenvironment / immunotherapy / multimodal integration

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