Journal of Modern Biotechnology Research
Journal of Modern Biotechnology Research. 2026; 4: (1) ; 10.12208/j.jmbr.20260001 .
总浏览量: 33
四川大学华西医院生物治疗科 四川成都;
*通讯作者： 冯唐,单位：四川大学华西医院生物治疗科 四川成都; ；
实体瘤是由肿瘤细胞、基质细胞、免疫成分、血管网络及细胞外基质共同参与的动态体系。如何在体外模型中更真实地重建这一复杂过程，是实体瘤基础研究、药物筛选和个体化治疗评估面临的重要问题。类器官，是一种能够保留患者来源肿瘤的部分组织结构、遗传特征和异质性的3D培养体系，为实体瘤研究提供了较传统二维培养更接近体内状态的模型。然而，单纯类器官体系仍难以充分模拟体内持续流动的营养交换、力学刺激、血管灌注以及免疫细胞参与的微环境调控过程，这也限制了其在肿瘤发生发展、侵袭转移和治疗反应研究中的解释力。微流控芯片技术为类器官模型提供了更加可控和动态的培养环境。类器官芯片通过整合微尺度流体控制、多细胞共培养、组织界面构建和实时检测等功能，使研究者能够在更接近生理状态的条件下观察肿瘤细胞与微环境之间的相互作用。近年来，该技术已逐渐应用于肺癌、肝癌、结直肠癌、乳腺癌及胰腺癌等多种实体瘤研究，在疾病建模、药物敏感性检测、转移过程模拟和个体化治疗预测方面显示出较大潜力。本文围绕类器官芯片的构建基础、关键技术和实体瘤研究应用进行综述，并进一步分析其在模型稳定性、血管化与免疫系统整合、检测标准化及临床转化方面仍需解决的问题。
Solid tumors are evolving tissue ecosystems shaped by tumor cells, stromal components, immune cells, vascular structures, extracellular matrix, and physical cues. This biological complexity has exposed the limitations of conventional in vitro models and has created a growing need for experimental systems that can better capture the dynamic nature of tumor development and therapeutic response. Organoids have substantially improved tumor modeling because they preserve, at least in part, the architecture, genetic features, and heterogeneity of patient-derived tissues. Nevertheless, organoids cultured under conventional static conditions remain incomplete representations of the in vivo tumor microenvironment. In particular, they often lack controlled fluid flow, vascular perfusion, immune participation, mechanical stimulation, and spatially organized tissue interfaces, all of which are essential for understanding tumor progression, invasion, metastasis, and drug resistance. The integration of organoids with microfluidic chip technology offers a practical way to address some of these limitations. Organoid-on-chip platforms allow precise regulation of fluid transport, multicellular co-culture, biochemical gradients, tissue–tissue interfaces, and real-time monitoring within a miniaturized and controllable system. These features make them especially valuable for investigating tumor–microenvironment interactions, evaluating drug sensitivity, modeling metastatic processes, and supporting patient-specific therapeutic assessment. In recent years, organoid-on-chip systems have been applied to a range of solid tumors, including lung, liver, colorectal, breast, and pancreatic cancers, where they have provided more physiologically relevant platforms for both mechanistic studies and translational research. In this review, we discuss the design principles, technical components, and major applications of organoid-on-chip platforms in solid tumor research. We also examine key barriers that continue to restrict their broader use, including reproducibility, long-term culture stability, vascular and immune integration, readout standardization, scalability, and clinical validation. Rather than considering organoid-on-chip systems as a simple extension of conventional organoid culture, we argue that they represent an important step toward dynamic reconstruction of tumor biology in vitro and may become a useful bridge between experimental cancer models and individualized treatment decision-making.
[1] Li, M. and J.C. Izpisua Belmonte, Organoids - Preclinical Models of Human Disease. N Engl J Med, 2019. 380(6): p. 569-579.
[2] Wensink, G.E., et al., Patient-derived organoids as a predictive biomarker for treatment response in cancer patients. NPJ Precis Oncol, 2021. 5(1): p. 30.
[3] Thng, D.K.H., et al., A functional personalised oncology approach against metastatic colorectal cancer in matched patient derived organoids. NPJ Precis Oncol, 2024. 8(1): p. 52.
[4] Yang, R. and Y. Yu, Patient-derived organoids in translational oncology and drug screening. Cancer Lett, 2023. 562: p. 216180.
[5] Lohmussaar, K., et al., Patient-derived organoids model cervical tissue dynamics and viral oncogenesis in cervical cancer. Cell Stem Cell, 2021. 28(8): p. 1380-1396 e6.
[6] Kjar, A., et al., Biofunctionalized gelatin hydrogels support development and maturation of iPSC-derived cortical organoids. Cell Rep, 2024. 43(11): p. 114874.
[7] Poletti, M., et al., Organoid-based Models to Study the Role of Host-microbiota Interactions in IBD. J Crohns Colitis, 2021. 15(7): p. 1222-1235.
[8] Zhu, Y., et al., Integrated characterization of hepatobiliary tumor organoids provides a potential landscape of pharmacogenomic interactions. Cell Rep Med, 2024. 5(2): p. 101375.
[9] Dao, V., et al., Immune organoids: from tumor modeling to precision oncology. Trends Cancer, 2022. 8(10): p. 870-880.
[10] Voabil, P., et al., An ex vivo tumor fragment platform to dissect response to PD-1 blockade in cancer. Nat Med, 2021. 27(7): p. 1250-1261.
[11] 屈晶晶, et al., 肿瘤类器官在癌症治疗中的协同应用、当前挑战和未来前景. 癌症, 2024. 43(10): p. 445-469.
[12] Yin, J., et al., Pancreatic islet organoids-on-a-chip: how far have we gone? J Nanobiotechnology, 2022. 20(1): p. 308.
[13] Duzagac, F., et al., Microfluidic Organoids-on-a-Chip: Quantum Leap in Cancer Research. Cancers (Basel), 2021. 13(4).
[14] Liang, R., et al., DNA methylation in lung cancer patients: Opening a "window of life" under precision medicine. Biomed Pharmacother, 2021. 144: p. 112202.
[15] Zhang, Z., et al., Expansion of CTCs from early stage lung cancer patients using a microfluidic co-culture model. Oncotarget, 2014. 5(23): p. 12383-97.
[16] 夏梦琳, 基于微流控-类器官技术构建猪源小肠类器官芯片模型. 2024.
[17] Zhu, Z., et al., Tissue/Organ Adaptable Bioelectronic Silk-Based Implants. Adv Mater, 2024. 36(38): p. e2405892.
[18] Paek, J., et al., Microphysiological Engineering of Self-Assembled and Perfusable Microvascular Beds for the Production of Vascularized Three-Dimensional Human Microtissues. ACS Nano, 2019. 13(7): p. 7627-7643.
[19] 杜宇, et al., 基于(类)器官芯片研究肝脏疾病的力学调控机制. 医用生物力学, 2024. 39(S1): p. 285.
[20] 蒋得明, 细胞与类器官传感器在抗肺癌药物评价和个体化治疗中的应用研究. 2021.
[21] Schuster, B., et al., Automated microfluidic platform for dynamic and combinatorial drug screening of tumor organoids. Nat Commun, 2020. 11(1): p. 5271.
[22] Dornhof, J., et al., Microfluidic organ-on-chip system for multi-analyte monitoring of metabolites in 3D cell cultures. Lab Chip, 2022. 22(2): p. 225-239.
[23] Nikolaev, M., et al., Homeostatic mini-intestines through scaffold-guided organoid morphogenesis. Nature, 2020. 585(7826): p. 574-578.
[24] Eiken, M.K., et al., Nascent matrix deposition supports alveolar organoid formation from aggregates in synthetic hydrogels. Stem Cell Reports, 2025. 20(1): p. 102376.
[25] Jacob, F., et al., A Patient-Derived Glioblastoma Organoid Model and Biobank Recapitulates Inter- and Intra-tumoral Heterogeneity. Cell, 2020. 180(1): p. 188-204 e22.
[26] Sato, T., et al., Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. Gastroenterology, 2011. 141(5): p. 1762-72.
[27] Shakeri, A., et al., Engineering Organ-on-a-Chip Systems for Vascular Diseases. Arterioscler Thromb Vasc Biol, 2023. 43(12): p. 2241-2255.
[28] Shan, H., et al., Acoustic virtual 3D scaffold for direct-interacting tumor organoid-immune cell coculture systems. Sci Adv, 2024. 10(47): p. eadr4831.
[29] Neophytou, C., T. Stylianopoulos, and F. Mpekris, The synergistic potential of mechanotherapy and sonopermeation to enhance cancer treatment effectiveness. NPJ Biol Phys Mech, 2025. 2(1): p. 13.
[30] Fang, G., et al., Enabling peristalsis of human colon tumor organoids on microfluidic chips. Biofabrication, 2021. 14(1).
[31] LeSavage, B.L., et al., Engineered matrices reveal stiffness-mediated chemoresistance in patient-derived pancreatic cancer organoids. Nat Mater, 2024. 23(8): p. 1138-1149.
[32] Worsdorfer, P. and S. Ergun, The Impact of Oxygen Availability and Multilineage Communication on Organoid Maturation. Antioxid Redox Signal, 2021. 35(3): p. 217-233.
[33] Jiang, C., et al., Collagen signaling and matrix stiffness regulate multipotency in glandular epithelial stem cells in mice. Nat Commun, 2024. 15(1): p. 10482.
[34] Sen, C., et al., Development of a small cell lung cancer organoid model to study cellular interactions and survival after chemotherapy. Front Pharmacol, 2023. 14: p. 1211026.
[35] Chen, M., et al., Mimicking Tumor Metastasis Using a Transwell-Integrated Organoids-On-a-Chip Platform. Small, 2024. 20(27): p. e2308525.
[36] Hu, Y., et al., Lung cancer organoids analyzed on microwell arrays predict drug responses of patients within a week. Nat Commun, 2021. 12(1): p. 2581.
[37] Liu, Yunhe et al. Molecular phenotypes and spatial archetypes: A new framework for cancer-associated fibroblasts. Cancer cell, 2026. 44(7):1346-1367.
[38] Chakrabarti, J., et al., Mouse-Derived Gastric Organoid and Immune Cell Co-culture for the Study of the Tumor Microenvironment. Methods Mol Biol, 2018. 1817: p. 157-168.
[39] Dijkstra, K.K., et al., Generation of Tumor-Reactive T Cells by Co-culture of Peripheral Blood Lymphocytes and Tumor Organoids. Cell, 2018. 174(6): p. 1586-1598 e12.
[40] Nofal, Z., et al., Recurring cycles of deprivation of serum and migration in confined spaces augments ganglioside SSEA-4 expression, boosting clonogenicity and cisplatin resistance in TNBC cell line. Sci Rep, 2025. 15(1): p. 16738.
[41] Li, J., et al., Construction of a metastasis model for liver cancer spheroids to hepatobiliary organoids facilitated by holographic acoustic tweezers. Cell Reports Physical Science, 2025. 6(6).
[42] Diao, X., et al., SUMOylation-triggered ALIX activation modulates extracellular vesicles circTLCD4-RWDD3 to promote lymphatic metastasis of non-small cell lung cancer. Signal Transduct Target Ther, 2023. 8(1): p. 426.
[43] Maiullari, F., et al., Modeling breast cancer dynamics through modulable small Vessel Environment Bioreactor (sVEB). Biomaterials, 2025. 323: p. 123441.
[44] Kastenschmidt, J.M., et al., A human lymphoma organoid model for evaluating and targeting the follicular lymphoma tumor immune microenvironment. Cell Stem Cell, 2024. 31(3): p. 410-420 e4.
[45] Pasch, C.A., et al., Patient-Derived Cancer Organoid Cultures to Predict Sensitivity to Chemotherapy and Radiation. Clin Cancer Res, 2019. 25(17): p. 5376-5387.
[46] Li, Z., et al., Patient-derived renal cell carcinoma organoids for personalized cancer therapy. Clin Transl Med, 2022. 12(7): p. e970.
[47] Du, Y., et al., Personalized Vascularized Tumor Organoid-on-a-Chip for Tumor Metastasis and Therapeutic Targeting Assessment. Adv Mater, 2025. 37(6): p. e2412815.
[48] Yan, X., et al., A high-throughput and logarithm‑ serial‑ dilution microfluidic chip for combinational drug screening on tumor organoids. ACS Pharmacol Transl Sci, 2024. 7(12), 4135–4143.
[49] Yakavets, I., et al., Machine learning-assisted exploration of multidrug-drug administration regimens for organoid arrays. Sci Adv, 2025. 11(31): eadt1851.
[50] Li, Y., et al., Multiplexed tumor-mimetic dECM-chip platform for colorectal cancer: Interrogating pharmacological synergy and NK cell immunosurveillance dynamics. Talanta, 2026. 298(Part B), 129012.
[51] Yao, N., et al., Patient-derived tumor organoids for cancer immunotherapy: culture techniques and clinical application. Invest New Drugs, 2025. 43(2): p. 394-404.
[52] Veith, I., et al., Assessing personalized responses to anti-PD-1 treatment using patient-derived lung tumor-on-chip. Cell Rep Med, 2024. 5(5): p. 101549.
[53] Yin, D., et al., A battery-free nanofluidic intracellular delivery patch for internal organs. Nature, 2025.
[54] Cheng, J., et al., ETV7 limits the antiviral and antitumor efficacy of CD8(+) T cells by diverting their fate toward exhaustion. Nat Cancer, 2025. 6(2): p. 338-356.
[55] Ouladan, S. and E. Orouji, Chimeric Antigen Receptor-T Cells in Colorectal Cancer: Pioneering New Avenues in Solid Tumor Immunotherapy. J Clin Oncol, 2025. 43(8): p. 994-1005.
[56] Yang, R., et al., Living biobank: Standardization of organoid construction and challenges. Chin Med J (Engl), 2024. 137(24): p. 3050-3060.
[57] Li, K., et al., Reproducible extracellular matrices for tumor organoid culture: challenges and opportunities. J Transl Med, 2025. 23(1): p. 497.
[58] Zhou, C., et al., Standardization of organoid culture in cancer research. Cancer Med, 2023. 12(13): p. 14375-14386.
[59] Kim, J.S., et al., Establishing 3D organoid models from patient-derived conditionally reprogrammed cells to bridge preclinical and clinical insights in pancreatic cancer. Mol Cancer, 2025. 24(1): p. 162.
[60] Gao, M., et al., Quantitatively Evaluating Interactions between Patient-Derived Organoids and Autologous Immune Cells by Microfluidic Chip. Anal Chem, 2024. 96(32): p. 13061-13069.
[61] Senkowski, W., et al., A platform for efficient establishment and drug-response profiling of high-grade serous ovarian cancer organoids. Dev Cell, 2023. 58(12): p. 1106-1121 e7.