Research Progress, Challenges, and Prospects of Primary Liver Cancer Organoids

We are writing this letter to share our insights on the research and application of primary liver cancer organoids (PLOs). Primary liver cancer (PLC), as one of the most prevalent and fatal malignant tumors worldwide, includes hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and mixed hepatocellular-cholangiocarcinoma, posing a significant threat to public health 1. For a long time, the lack of a reliable preclinical model that can accurately reproduce the clinical tumor heterogeneity and biological characteristics has been a bottleneck in the development of effective diagnosis and treatment strategies for PLC. In recent years, PLOs, as a new three-dimensional in vitro culture system, have shown great potential in overcoming this limitation and have thus attracted widespread attention in the field of oncology. PLOs originate from the tumor tissues or cancer stem cells of patients with primary liver cancer and can be cultured in vitro for a long time while retaining the key biological characteristics of the primary tumor, such as histological structure, genetic heterogeneity, and expression profiles of tumor markers 2. Compared with traditional two-dimensional cell lines and animal models, PLOs have significant advantages. First, they can better simulate the tumor microenvironment in vivo and more accurately reflect the response of tumor cells to drugs; second, they can be established based on individual patients, providing a personalized platform for drug sensitivity testing and precision medicine; third, they can be used to explore the mechanisms of primary liver cancer, such as the role of cancer stem cells and the interaction between tumor cells and the microenvironment. Compared with patient-derived xenograft models, the emergence of organoids has greatly increased the success rate of primary liver cancer modeling, while maintaining tumor heterogeneity characteristics and enabling individualized treatment 3. Broutier et al. studied a system including PLC-derived organoid culture, which can retain the histological results, gene expression, and genomic manifestations of the original tumor, enabling faster high-throughput drug screening and having great potential to benefit PLC patients 4. In terms of clinical application, PLOs have demonstrated broad prospects in multiple fields 5. For instance, in drug screening, PLOs can be used to predict the efficacy of chemotherapy drugs, targeted drugs, and immunotherapy drugs for individual patients, assisting clinicians in formulating personalized treatment plans and avoiding ineffective treatments and unnecessary side effects 6. Moreover, PLOs can also serve as a tool for exploring new therapeutic targets and developing new drugs, accelerating the translation of basic research results into clinical practice 7. However, although PLOs research has made significant progress, there are still some challenges that need to be addressed urgently. Firstly, the components of the in vitro culture system for PLOs are complex, and there is a lack of standardized culture protocols, which may lead to differences in biological characteristics among PLOs established by different laboratories, thereby affecting the reproducibility of research results. Second, the current PLOs models mainly focus on tumor cells and often can only simulate part of the structure and function of real organs. Compared with animal models, they lack functional vascular systems, neural networks, and the interaction of immune cells. Third, the cost of PLOs culture is high, and their clinical transformation is still at an early stage. More large-scale clinical studies are needed to verify their predictive value and clinical practicability. In conclusion, PLOs have become a powerful tool for primary liver cancer research, with broad application prospects in precision medicine, drug development, and prognosis prediction. Although there are still many challenges, with the continuous improvement of cultivation techniques and in-depth research, we believe that in the near future, PLOs will play an increasingly important role in improving the diagnosis and treatment level of primary liver cancer and benefiting more patients. Zhenxiao Wang: conceptualization, investigation, writing – original draft, writing – review and editing. Shui Liu: conceptualization, methodology, investigation, project administration, funding acquisition, writing – original draft, writing – review and editing. We thank the authors of the papers published in this research topic for their valuable contributions and the referees for their rigorous review. The authors have nothing to report. The authors have nothing to report. The authors declare no conflicts of interest. Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.