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CORRECTION article

Front. Bioeng. Biotechnol.

Sec. Organoids and Organ-On-A-Chip

Volume 13 - 2025 | doi: 10.3389/fbioe.2025.1671862

This article is part of the Research TopicInnovative Organoid Co-Culture Systems for Enhanced Precision Medicine in Cancer and BeyondView all 4 articles

Correction:Organoids in Cancer Therapies: A Comprehensive Review

Provisionally accepted
  • 1Hangzhou Medical College, Hangzhou, China
  • 2Ningbo No 2 Hospital, Ningbo, China

The final, formatted version of the article will be published soon.

Cancer continues to represent a significant threat to life and a major risk factor for morbidity and mortality on a global scale (1) in spite of the remarkable advancements in cancer research, diagnosis, detection and treatment made in recent decades . Currently, the most commonly used cancer models for research include human cancer cell lines, animal tumor tissue transplantation models and organoid models, which have been proposed in the last decade. This comprehensive review aims to synthesize recent breakthroughs in tumor organoid technology, evaluate its transformative role in overcoming the constraints of existing models, and delineate how organoids are reshaping precision medicine in cancer therapy.An organoid is a combination of organ-specific cell types developed from stem cells or organ progenitor cells and organized in an organ-specific manner that emulates the process of in vivo cell sorting and spatial lineage qualification (2). This process exhibits three characteristics: (i) Specificity: The presence of specific cell types from different organs; (ii) Functionality: The ability to perform the functions of organs, including contraction, secretion, filtration, and so on; and (iii) Spatiality:Immortalized cancer cell lines, while widely accessible, undergo genetic drift during long-term culture, losing the heterogeneity and microenvironmental context of original tumors (3). This compromises their predictive value for clinical drug responses.In comparison to human cancer cell lines, organoids exhibit greater stability, less prone to undergo genetic alterations and heterogeneity during cell proliferation.Studies have demonstrated that following the sequencing of cancer-related genes in colon tumor organoid models and their primitive tumors, there is a 90% similarity between the organoid models and biopsies in terms of somatic mutations and DNA copy number (4). This confirms that organoids are capable of maintaining. Animal xenograft models suffer from interspecies differences in tumor-stroma interactions, immune responses, and drug metabolism. Their high cost, prolonged timelines, and ethical constraints further limit scalability for high-throughput studies (5). In comparison to animal models, organoids offer a more cost-effective, time-efficient, and genetically stable alternative (6). Despite their inability to restore immune system interactions during natural proliferation, they provide a valuable research tool for studying cancer biology.The cultivation of tumor-derived organoids from tissue-or tumor-specific stem cells is dependent on the advancement of three-dimensional (3D) culture technology.One of the earliest known tumor-derived organoids was developed by Sato et al. The culture environment was adapted to achieve unlimited proliferation and spatial arrangement of tumor cells based on the culture conditions of mouse colonic crypts. This was achieved by adding Wnt3A, nicotinamide, as well as Alk small molecule inhibitors and p38 inhibitors (7). To date, successful tumor organoid models have been cultured, including those derived from colon carcinoma (8), Prostate carcinoma (9), gastric carcinoma (10), Renal carcinoma (11) and Head and Neck squamous cell carcinoma (12). Based on the simulation of pathological mechanisms of tumor development and mutations in different signaling pathways, tumor organoids have demonstrated considerable potential in anti-cancer drug screening and personalized medicine. Despite the nascent state of organoid applications in guiding clinical treatment, there is a growing demand for the use of tumor organoids to inform patient treatment. Millions of cancer cells and their embedded tumor-associated microenvironments collectively constitute a tumor, which exhibits heterogeneity that can influence cancer progression and create some resistance to clinical therapy. Taken together, intratumor heterogeneity is the result of a complex, multifactorial-driven integration of genetic genomic, epimolecular, and microenvironmental changes. (13) At present, there is no clear conclusion on the molecular mechanism of tumorigenesis, and we hope to elucidate its heterogeneous developmental progression with the help of clinical models and seek new treatment options. For example, Mo et al. (14) demonstrated that organoids are able to capture tumor heterogeneity between patients and individuals by constructing a biobank of organoids from primary colorectal cancer with liver metastasis and analyzing them comprehensively at the multi-omics level. As another example, Jacob et al. (15) constructed patient-derived glioblastoma-like organoids (GBOs) and confirmed the ability of the organoids to retain inter-versus intratumor transcriptomic and genomic heterogeneity to a high degree by comparing the cell types and molecular features of the parent tumors. In conclusion, living organoid biobanks constructed using patient-derived tumor cells can provide powerful credentials and abundant resources for studying the molecular heterogeneity and biological behavioral characteristics of cancer at the genetic level.Tumor development is not only subject to the transformative and regulatory effects of genetic and molecular phenotypes of normal cells, but also requires the infiltration of a highly abnormal microenvironment (13).Among them, tumor-associated microenvironment(TME)consists of vascular tissues and lymphatic networks, fibroblasts, various immune cell subpopulations, extracellular matrix, and various signaling factors in and around the tumor (16),which plays a crucial role in sustaining the cancer process. Therefore, the use of organoid technology to mimic the corresponding tumor microenvironment to construct "immune-tumor organoids" has a good application prospect to explore the development of cancer.However, as of now, traditional organoid models are unable to replicate the stromal components of the parental cells including the various immune cell subpopulations therein (17), and there is an urgent need to introduce the cellular components of TME environments in order to better mimic the corresponding microenvironmental dynamics systems. Several co-culture strategies are available today in an attempt to mimic the corresponding tumor microenvironment, with direct co-culture, microfluidic 3D culture, and ALI culture being the three main methods.these methods each have their own advantages and disadvantages(18)(Table1). However,traditional Matrigel-embedding systems rely predominantly on passive diffusion for nutrient/waste exchange,a process severely constrained by increasing organoid size (20).To address this,microfluidic 3D culture platforms have emerged.These systems employ microfluidic chips featuring a central gel chamber flanked by bilateral perfusion channels.Operationally,cell-Matrigel mixtures are injected into the central chamber,while culture media are perfused through adjacent channels (21).This design enables microscale modeling and functional integration through high-density tumor cell seeding within microporous architectures.Both Matrigel-embedding and microfluidic approaches require exogenous immune cell supplementation to reconstruct the tumor microenvironment (TME).In contrast,the air-liquid interface(ALI) culture establishes a biphasic system using Transwell inserts.Tumor fragments embedded in collagen matrices are exposed to air in the upper chamber(gas phase),while basal nutrients diffuse upward through microporous membranes from serum-supplemented media below(liquid phase) (22).Critically,ALI ' s non-enzymatic processing and biphasic design optimally preserve native immune components,positioning it as the gold standard for in situ TME modeling.As Dijkstra et al. (23)have established an organoid model of a tumor-like microenvironment, which is a co-culture system containing IL-2 mediators using anti-CD28 and anti-PD-1(Programmed Death-1,PD-1)antibodies against peripheral blood mononuclear cells(Peripheral blood mononuclear cells (PBMC) were stimulated with anti-CD28 and anti-PD-1(Programmed Death-1,PD-1)antibodies to induce the generation of lymphocytes, which were then co-cultured with interferon-γ (IFN-γ ) pretreated monocyte suspensions. In the process of exploring the optimal solution of the co-culture method, the researchers found that the components contained in the medium could theoretically penetrate the stromal gel and mimic the biological processes in the patient's body, but in reality, it is difficult for the immune cells, which are the main components, to penetrate the stromal gel and interact with the tumor. Although the ALI method can directly reconstruct the natural stroma and immune environment, which more realistically resembles the internal environment of the human body, the immune components are depleted over time, and it is still unable to provide a stable survival environment for organoids for a long period of time (18).In fact, in addition to the immune cell component, the vascular component and the fibroblast component are also indispensable components of cancer organoid mimicking the tumor microenvironment (18).As far as the current organoid models are concerned, the experiments are still insufficient to make up for the above three components, such as the maintenance of the culture environment is not stable for a long period of time, and the co-culture conditions still need to be optimized, which is still a major challenge for the development of "immune-tumor" organoid. For the currently established organoid model, it is still insufficient to compensate for the above three components in the experiments, such as the maintenance of the culture environment is not stable for a long period of time, the cost of the culture cycle is too high, and the co-culture conditions still need to be optimized, which is still a major test for the development of "immune-tumor" organoid. Cancer formation, development, deterioration and metastasis is an interrelated multifactorial and gradual process, and the establishment of the corresponding tumor organoid biobank model can help us to understand the specific mechanism of cancer at different stages of evolution, which is of great significance for clinical screening and diagnosis, prevention and treatment.On the one hand, some infectious agents have been recognized as important risk factors for cancer, such as gastric cancer and Helicobacter pylori, gallbladder cancer and Salmonella enterica, liver cancer and hepatitis viruses, as well as nasopharyngeal cancer, gastric cancer and lymphoma and EBV. However, the exact mechanism of association as well as the causal relationship is not yet clear, and we would like to explore the exact process with the help of organoid-pathogen binding co-culture (24).For example, Buti et al. (25),by constructing a co-culture system of H.pylori with gastric organs, found that its virulence factor, CagA, bound to the Apoptosis stimulating protein of p53-2 (ASPP2) to form a complex ASPP2 induces the remodeling of cell polarity complexes, resulting in the loss of cell polarity and the Tumor-derived sphere culture method is currently one of the more applied and In summary, organoid models have shown promising application prospects in simulating tumor heterogeneity and tracking cancer stem cells, which is conducive to promoting drug resistance screening and precision medicine(Figure 1). Organoids, as individualized clinical models, can provide personalized medication guidance through drug sensitivity testing, to improve treatment response rates and reduce chemotherapy toxicity (47). FAN (48) Precision medicine requires the identification of biomarkers to screen patients for benefit, and current assessments of key target expression or genetic abnormalities, while diagnostic, prognostic, and predictive, have limitations, such as lack of selectivity in molecular characterization and limited interpretation. (62) In contrast, organoid testing in precision medicine can determine the correlation between response to ex vivo therapy and the presence of predictive biomarkers of different types (e.g., DNA, messenger RNA, noncoding RNA, and proteins, as well as other biomarkers)and sources (e.g., tumor, blood, and urine, as well as other sources).( 58 demonstrated that the reproducibility of organoid culture can vary under identical conditions (69). It has been postulated that this may be attributable to the utilization of disparate batches of serum during the construction of the models. In particular, foetal bovine serum (FBS) derived from the blood of foetal cows comprises a multitude of peptides, proteins, lipids, hormones, carbohydrates and small molecule nutrients (70).The harvesting of serum is subject to seasonal and geographic variations, which result in discrepancies in the concentration of soluble components between suppliers and batches. In order to achieve consistency, synthetic materials such as HA, PEG and gelatin have been widely developed as substrates for organoid cultures (71).Consequently, future research must identify the factors that contribute to the generation of reproducible organoids. Otherwise, such variability limits the reproducibility of organoid cultures on a large scale and inhibits the potential application of organoids in high-throughput drug screening. The second factor is the lack of vascularization, which can be defined as imperfections in the microenvironmental components. PODs can be used not only to screen patients for abnormalities and select individualized treatment regimens, but also to predict the patient's response to chemotherapy and targeted therapies. Furthermore, organoid technology can be employed to predict a patient's response to chemotherapy and targeted therapies. In the study conducted by Vlach Giannis et al (60)., patient-derived organoid organ models were utilized to simulate treatment response in metastatic gastrointestinal cancer, thereby providing a powerful tool for personalized medicine. With the continuous advancement and optimization of this technology, it is reasonable to believe that organoid technology will play an even more important role in future biomedical research and clinical treatment.Nevertheless, fundamental research on organoids is still confronted with a number of previous obstacles before genuinely and extensively employed in cancer therapy. Firstly, the majority of organoids are derived from epithelial cancers, and there is a paucity of knowledge regarding tumors of other tissue types. However, glioblastoma organoids have been reported (74). Secondly, the efficiency and purity of organoid culture must be enhanced, which is essential for high-throughput screening of drugs and precision therapy. Thirdly, the co-cultivation of organoids and microorganisms requires further investigation when examining the relationship between tumors and pathogens. Exploration has also been conducted, combining intestinal organoid culture with peripheral microinjection techniques (75). Finally, organoid research also raises additional ethical issues that require revisiting and potentially recalibrating ethical and legal policies (76).In the future, research on cancer-derived organoids will be deepened in a number of areas, including model construction, drug response, and precision therapy.Additionally, research will be conducted into emerging technologies designed to enhance the utility of organoids and the integration of organoids with other 'omics' data (77). This data can be used in systems biology to improve the ability to analyze the results of experiments in a systematic way. Furthermore, the utilization of

Keywords: organoids1, Cancer therapy2, Disease modeling3, Drug Screening4, personalized medicine5

Received: 23 Jul 2025; Accepted: 31 Jul 2025.

Copyright: © 2025 Jiang, Wang, Di, Qian and Haitao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Xinyi Jiang, Hangzhou Medical College, Hangzhou, China
Jiang Haitao, Hangzhou Medical College, Hangzhou, China

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