Organoids are three-dimensional (3D) cell-culture systems derived from stem cells or malignant cells that closely mimic the architecture and physiological function of native organs in vitro. By providing a high-fidelity representation of in vivo disease states, these systems hold significant potential for advancing disease modeling, pharmacological screening, and personalized medicine, as well as for investigating complex biological processes.

A recent review in the Genes & Diseases journal by researchers from Xiamen University and collaborating institutions explores the potential applications and challenges of utilizing organoids in ESCC research. Despite advancements in neoadjuvant chemoradiotherapy and endoscopic techniques, surgery remains the primary treatment modality. The review elucidates how multifactorial drug resistance and the tumor microenvironment (TME) contribute to the poor prognosis of ESCC, highlighting the urgent need for reliable 3D tumor models and biorepositories to uncover these mechanisms and identify novel therapeutic targets to overcome chemoresistance.

The authors evaluate the strengths and limitations of various in vitro and ex vivo tumor models, including 2D cell cultures, 3D spheroids, ex vivo tissue slices, and microfluidic chip systems. Among these, patient-derived organoids (PDOs) are highlighted as "clinical avatars" for predicting drug sensitivity and evaluating treatment efficacy. The integration of organoid technology with CRISPR/Cas9 gene editing further enables the validation of specific genetic mutations and signaling pathways that drive oncogenesis and therapeutic resistance.

Beyond genomic modeling, organoids are essential for studying the TME through advanced co-cultures with immune cells and fibroblasts. These systems provide insights into tumor-immune interactions, facilitate the development of personalized immunotherapies, and enable real-time monitoring of drug resistance. Despite challenges in scalability, advancements in micro-engineered platforms are establishing organoids as a primary tool for precision medicine and biomarker discovery.

Although PDOs closely recapitulate patient-specific responses, several barriers—including protracted culture timelines, variable success rates, and poor reproducibility—hinder their routine clinical implementation. The review also identifies additional bottlenecks, such as the lack of unified data repositories, the biological simplicity of models lacking key TME components, and high costs. Ultimately, optimized co-culture systems and prospective cohort studies are required to validate the correlation between organoid-based testing and clinical outcomes, advancing personalized medicine in ESCC.

In conclusion, organoids bridge the gap between in vitro research and clinical practice by replicating the genomic landscape and functional heterogeneity of ESCC. However, widespread clinical integration necessitates standardized protocols, cost reduction, and enhanced biological complexity to better simulate the tumor microenvironment.

Reference

Title of the original paper: The advancements in organoids: Potential and challenges in researching the esophagus and esophageal squamous cell carcinoma

Journal : Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101680

Funding Information:

1. National Natural Science Foundation of China (No. 82273044)
2. Science Fund for Distinguished Young Scholars of Fujian Province, China (No. 2021D034)
3. Science Fund from the Health Commission of Fujian, China (No. 2023GGB04)
4. Clinical Investigation Program from the 900 Hospital (China) (No. 2020L09)

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