Organoid: a promising solution to current challenges in cancer immunotherapy

Organoid: a promising solution to current challenges in cancer immunotherapy

  • Liu, Y. et al. Chimeric STAR receptors using TCR machinery mediate robust responses against solid tumors. Sci. Transl. Med. 13, eabb5191 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Magré, L. et al. Emerging organoid-immune co-culture models for cancer research: from oncoimmunology to personalized immunotherapies. J. Immunother. Cancer 11, e006290 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Duan, Z. et al. CAR-T cells based on a TCR mimic nanobody targeting HPV16 E6 exhibit antitumor activity against cervical cancer. Mol. Ther.: Oncol. 32, 200892 (2024).

    CAS 
    PubMed 

    Google Scholar
     

  • Liu, L. et al. Engineering sonogenetic EchoBack-CAR T cells. Cell 188, 2621–2636.e20 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lu, Y.-C. et al. Treatment of patients with metastatic cancer using a major histocompatibility complex class II–restricted T-cell receptor targeting the cancer germline antigen MAGE-A3. JCO 35, 3322–3329 (2017).

    Article 
    CAS 

    Google Scholar
     

  • Hong, D. S. et al. Phase I dose escalation and expansion trial to assess the safety and efficacy of ADP-A2M4 SPEAR T cells in advanced solid tumors. JCO 38, 102–102 (2020).

    Article 

    Google Scholar
     

  • Liu, M. et al. MAGE-A4 pMHC-targeted CAR-T cells exploiting TCR machinery exhibit significantly improved in vivo function while retaining antigen specificity. J. Immunother. Cancer 12, e010248 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Van Norman, G. A. Limitations of animal studies for predicting toxicity in clinical trials. JACC: Basic Transl. Sci. 4, 845–854 (2019).

    PubMed 

    Google Scholar
     

  • Atkins, J. T. et al. Pre-clinical animal models are poor predictors of human toxicities in phase 1 oncology clinical trials. Br. J. Cancer 123, 1496–1501 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sharma, P., Hu-Lieskovan, S., Wargo, J. A. & Ribas, A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168, 707–723 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Galon, J. & Bruni, D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat. Rev. Drug Discov. 18, 197–218 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gu, S. S. et al. Clonal tracing reveals diverse patterns of response to immune checkpoint blockade. Genome Biol. 21, 263 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Morad, G., Helmink, B. A., Sharma, P. & Wargo, J. A. Hallmarks of response, resistance, and toxicity to immune checkpoint blockade. Cell 184, 5309–5337 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fennema, E., Rivron, N., Rouwkema, J., Van Blitterswijk, C. & De Boer, J. Spheroid culture as a tool for creating 3D complex tissues. Trends Biotechnol. 31, 108–115 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Fang, G., Chen, Y., Lu, H. & Jin, D. Advances in spheroids and organoids on a chip. Adv. Funct. Mater. 33, 2215043 (2023).

    Article 
    CAS 

    Google Scholar
     

  • Zhang, B. & Radisic, M. Organ-on-a-chip devices advance to market. Lab Chip 17, 2395–2420 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Leung, C. M. A guide to the organ-on-a-chip. Nat. Rev. Methods Primers 2 (2022).

  • Bar-Ephraim, Y. E., Kretzschmar, K. & Clevers, H. Organoids in immunological research. Nat. Rev. Immunol. 20, 279–293 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hofer, M. & Lutolf, M. P. Engineering organoids. Nat. Rev. Mater. 6, 402–420 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhao, Z. et al. Organoids. Nat. Rev. Methods Prim. 2, 94 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Wagar, L. E. Human immune organoids: a tool to study vaccine responses. Nat. Rev. Immunol. 23, 699–699 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Polak, R., Zhang, E. T. & Kuo, C. J. Cancer organoids 2.0: modelling the complexity of the tumour immune microenvironment. Nat. Rev. Cancer 24, 523–539 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tang, X.-Y. et al. Human organoids in basic research and clinical applications. Sig Transduct. Target Ther. 7, 168 (2022).

    Article 

    Google Scholar
     

  • Ingber, D. E. Human organs-on-chips for disease modelling, drug development and personalized medicine. Nat. Rev. Genet. 23, 467–491 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nakamura, T. & Sato, T. Advancing intestinal organoid technology toward regenerative. Med. Cell. Mol. Gastroenterol. Hepatol. 5, 51–60 (2018).

    Article 

    Google Scholar
     

  • Huang, R., Gao, F., Yu, L., Chen, H. & Zhu, R. Generation of neural organoids and their application in disease modeling and regenerative medicine. Adv. Sci. 12, e01198 (2025).

    Article 
    CAS 

    Google Scholar
     

  • Zheng, M., Erice, E., Wang, H., Zhang, L. & Lawrie, C. H. Organoid-on-a-chip (OrgOC): advancing cystic fibrosis research. Mater. Today Bio 34, 102148 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhao, J. et al. APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids. Nat. Commun. 11, 5540 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu, X. et al. Analogous comparison unravels heightened antiviral defense and boosted viral infection upon immunosuppression in bat organoids. Sig Transduct. Target Ther. 7, 392 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Li, P. et al. Mpox virus infection and drug treatment modelled in human skin organoids. Nat. Microbiol. 8, 2067–2079 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Takebe, T. & Wells, J. M. Organoids by design. Science 364, 956–959 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhao, Y. et al. Integrating organoids and organ-on-a-chip devices. Nat. Rev. Bioeng. 2, 588–608 (2024).

    Article 
    CAS 

    Google Scholar
     

  • Kim, J. M. & Chen, D. S. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann. Oncol. 27, 1492–1504 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kim, R., Emi, M. & Tanabe, K. Cancer immunoediting from immune surveillance to immune escape. Immunology 121, 1–14 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Angelova, M. et al. Evolution of metastases in space and time under immune selection. Cell 175, 751–765.e16 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • TRACERx consortium, T. he et al. Neoantigen-directed immune escape in lung cancer evolution. Nature 567, 479–485 (2019).

    Article 

    Google Scholar
     

  • Philip, M. & Schietinger, A. CD8+ T cell differentiation and dysfunction in cancer. Nat. Rev. Immunol. 22, 209–223 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wolf, Y. et al. UVB-induced tumor heterogeneity diminishes immune response in melanoma. Cell 179, 219–235.e21 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Klempner, S. J. et al. Tumor mutational burden as a predictive biomarker for response to immune checkpoint inhibitors: a review of current evidence. Oncologist 25, e147–e159 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Ricciuti, B. et al. Association of high tumor mutation burden in non–small cell lung cancers with increased immune infiltration and improved clinical outcomes of PD-L1 blockade across PD-L1 expression levels. JAMA Oncol. 8, 1160 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wolf, Y. & Samuels, Y. Intratumor heterogeneity and antitumor immunity shape one another bidirectionally. Clin. Cancer Res. 28, 2994–3001 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Aggarwal, C. et al. Assessment of tumor mutational burden and outcomes in patients with diverse advanced cancers treated with immunotherapy. JAMA Netw. Open 6, e2311181 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • McGrail, D. J. et al. High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types. Ann. Oncol. 32, 661–672 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hellmann, M. D. et al. Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer. Cancer Cell 33, 843–852.e4 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Samstein, R. M. et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat. Genet. 51, 202–206 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chan, T. A. et al. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann. Oncol. 30, 44–56 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Terry, S. et al. New insights into the role of EMT in tumor immune escape. Mol. Oncol. 11, 824–846 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Malagoli Tagliazucchi, G., Wiecek, A. J., Withnell, E. & Secrier, M. Genomic and microenvironmental heterogeneity shaping epithelial-to-mesenchymal trajectories in cancer. Nat. Commun. 14, 789 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • He, R. et al. Progress in the application of immune checkpoint inhibitor-based immunotherapy for targeting different types of colorectal cancer. Front. Oncol. 11, 764618 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chowdhury, S. et al. Consensus molecular subtyping of metastatic colorectal cancer expands biomarker-directed therapeutic benefit for patients with CMS1 and CMS2 tumors. Br. J. Cancer 131, 1328–1339 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pickup, M., Novitskiy, S. & Moses, H. L. The roles of TGFβ in the tumour microenvironment. Nat. Rev. Cancer 13, 788–799 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Karamitopoulou, E. Tumour microenvironment of pancreatic cancer: immune landscape is dictated by molecular and histopathological features. Br. J. Cancer 121, 5–14 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bear, A. S. et al. Biochemical and functional characterization of mutant KRAS epitopes validates this oncoprotein for immunological targeting. Nat. Commun. 12, 4365 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fridman, W. H., Pagès, F., Sautès-Fridman, C. & Galon, J. The immune contexture in human tumours: impact on clinical outcome. Nat. Rev. Cancer 12, 298–306 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Dijkstra, K. K. et al. Generation of tumor-reactive t cells by co-culture of peripheral blood lymphocytes and tumor organoids. Cell 174, 1586–1598.e12 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Andel, D. et al. Pre-existing subclones determine radioresistance in rectal cancer organoids. Cell Rep. 43, 113735 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kratz, J. D. et al. Subclonal response heterogeneity to define cancer organoid therapeutic sensitivity. Sci. Rep. 15, 12072 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mai, Z., Lin, Y., Lin, P., Zhao, X. & Cui, L. Modulating extracellular matrix stiffness: a strategic approach to boost cancer immunotherapy. Cell Death Dis. 15, 307 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, J. C. et al. The liver-immunity nexus and cancer immunotherapy. Clin. Cancer Res 28, 5–12 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, Q. et al. Differential organ-specific tumor response to first-line immune checkpoint inhibitor therapy in non-small cell lung cancer—a retrospective cohort study. Transl. Lung Cancer Res. 12, 312–321 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Damsky, W. et al. B cell depletion or absence does not impede anti-tumor activity of PD-1 inhibitors. J. Immunother. Cancer 7, 153 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Griss, J. et al. B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma. Nat. Commun. 10, 4186 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Helmink, B. A. et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 577, 549–555 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Thorsson, V. et al. The Immune landscape of cancer. Immunity 48, 812–830.e14 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Boussiotis, V. A. et al. Activated human B lymphocytes express three CTLA-4 counterreceptors that costimulate T-cell activation. Proc. Natl Acad. Sci. USA 90, 11059–11063 (1993).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Keir, M. E., Butte, M. J., Freeman, G. J. & Sharpe, A. H. PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 26, 677–704 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yang, Y. et al. CTLA-4 expression by B-1a B cells is essential for immune tolerance. Nat. Commun. 12, 525 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jain, R. K. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26, 605–622 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kabir, A. U., Subramanian, M., Kwon, Y. & Choi, K. Linking tumour angiogenesis and tumour immunity. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-025-01211-z (2025).

  • Levental, K. R. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891–906 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Martin, J. D., Seano, G. & Jain, R. K. Normalizing function of tumor vessels: progress, opportunities, and challenges. Annu. Rev. Physiol. 81, 505–534 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • D’Andrea, M. R. et al. Propensity for early metastatic spread in breast cancer: role of tumor vascularization features and tumor immune infiltrate. Cancers 13, 5917 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ley, K., Laudanna, C., Cybulsky, M. I. & Nourshargh, S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat. Rev. Immunol. 7, 678–689 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hamzah, J. et al. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 453, 410–414 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ene–Obong, A. et al. Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma. Gastroenterology 145, 1121–1132 (2013).

    Article 
    PubMed 

    Google Scholar
     

  • Woods, A. N. et al. Differential expression of homing receptor ligands on tumor-associated vasculature that control CD8 effector t-cell entry. Cancer Immunol. Res. 5, 1062–1073 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Heldin, C.-H., Rubin, K., Pietras, K. & Östman, A. High interstitial fluid pressure—an obstacle in cancer therapy. Nat. Rev. Cancer 4, 806–813 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gabrilovich, D. I., Ostrand-Rosenberg, S. & Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12, 253–268 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Anczuków, O. et al. Challenges and opportunities for modeling aging and cancer. Cancer Cell 41, 641–645 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gal-Oz, S. T. et al. ImmGen report: sexual dimorphism in the immune system transcriptome. Nat. Commun. 10, 4295 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Márquez, E. J. et al. Sexual-dimorphism in human immune system aging. Nat. Commun. 11, 751 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fane, M. & Weeraratna, A. T. How the ageing microenvironment influences tumour progression. Nat. Rev. Cancer 20, 89–106 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chen, A. C. Y. et al. The aged tumor microenvironment limits T cell control of cancer. Nat. Immunol. 25, 1033–1045 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dolan, M., Libby, K. A., Ringel, A. E., Van Galen, P. & McAllister, S. S. Ageing, immune fitness and cancer. Nat. Rev. Cancer 25, 848–872 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Liu, Z. et al. Immunosenescence: molecular mechanisms and diseases. Sig Transduct. Target Ther. 8, 200 (2023).

    Article 
    CAS 

    Google Scholar
     

  • Hu, J., Pan, M., Reid, B., Tworoger, S. & Li, B. Quantifiable blood TCR repertoire components associate with immune aging. Nat. Commun. 15, 8171 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fransen, F. et al. Aged gut microbiota contributes to systemical inflammaging after transfer to germ-free mice. Front. Immunol. 8, 1385 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Acerbi, I. et al. Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integr. Biol. 7, 1120–1134 (2015).

    Article 
    CAS 

    Google Scholar
     

  • Calhoun, C. et al. Senescent cells contribute to the physiological remodeling of aged lungs. GERONA 71, 153–160 (2016).

    Article 
    CAS 

    Google Scholar
     

  • Tsukita, Y. et al. Immunotherapy or chemoimmunotherapy in older adults with advanced non–small cell lung cancer. JAMA Oncol. 10, 439 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Kao, C. et al. Age-related divergence of circulating immune responses in patients with solid tumors treated with immune checkpoint inhibitors. Nat. Commun. 16, 3531 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kugel, C. H. et al. Age correlates with response to anti-PD1, reflecting age-related differences in intratumoral effector and regulatory T-cell populations. Clin. Cancer Res. 24, 5347–5356 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hamilton, J. A. G. & Henry, C. J. Aging and immunotherapies: new horizons for the golden ages. Aging Cancer 1, 30–44 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Johnson, D. B., Sullivan, R. J. & Menzies, A. M. Immune checkpoint inhibitors in challenging populations. Cancer 123, 1904–1911 (2017).

    Article 
    PubMed 

    Google Scholar
     

  • Loizides, S. & Papamichael, D. Considerations and challenges in the management of the older patients with gastric cancer. Cancers 14, 1587 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tran Van Hoi, E. et al. Blood based immune biomarkers associated with clinical frailty scale in older patients with melanoma receiving checkpoint inhibitor immunotherapy. Immun. Ageing 21, 83 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Day, C.-P., Merlino, G. & Van Dyke, T. Preclinical mouse cancer models: a maze of opportunities and challenges. Cell 163, 39–53 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rehli, M. Of mice and men: species variations of Toll-like receptor expression. Trends Immunol. 23, 375–378 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mestas, J. & Hughes, C. C. W. Of mice and not men: differences between mouse and human immunology. J. Immunol. 172, 2731–2738 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Huang, L., Xu, H. & Peng, G. TLR-mediated metabolic reprogramming in the tumor microenvironment: potential novel strategies for cancer immunotherapy. Cell Mol. Immunol. 15, 428–437 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Huang, B., Zhao, J., Unkeless, J. C., Feng, Z. H. & Xiong, H. TLR signaling by tumor and immune cells: a double-edged sword. Oncogene 27, 218–224 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Song, I. J. et al. The contribution of toll-like receptor signaling to the development of liver fibrosis and cancer in hepatocyte-specific TAK1-deleted mice. Int. J. Cancer 142, 81–91 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Fischer, M. Mice are not humans: the case of p53. Trends Cancer 7, 12–14 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Frank, M. L. et al. T-cell receptor repertoire sequencing in the era of cancer immunotherapy. Clin. Cancer Res. 29, 994–1008 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zomer, H. D. & Trentin, A. G. Skin wound healing in humans and mice: challenges in translational research. J. Dermatol. Sci. 90, 3–12 (2018).

    Article 
    PubMed 

    Google Scholar
     

  • Allison, J. P. & Havran, W. L. The immunobiology of T cells with invariant gammadelta antigen receptors. Annu. Rev. Immunol. 9, 679–705 (1991).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kupper, T. S. & Fuhlbrigge, R. C. Immune surveillance in the skin: mechanisms and clinical consequences. Nat. Rev. Immunol. 4, 211–222 (2004).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nagao, K. et al. Stress-induced production of chemokines by hair follicles regulates the trafficking of dendritic cells in skin. Nat. Immunol. 13, 744–752 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pasparakis, M., Haase, I. & Nestle, F. O. Mechanisms regulating skin immunity and inflammation. Nat. Rev. Immunol. 14, 289–301 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lewis, S. M., Williams, A. & Eisenbarth, S. C. Structure and function of the immune system in the spleen. Sci. Immunol. 4, eaau6085 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sittig, L. J. et al. Genetic background limits generalizability of genotype-phenotype relationships. Neuron 91, 1253–1259 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Beura, L. K. et al. Normalizing the environment recapitulates adult human immune traits in laboratory mice. Nature 532, 512–516 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rosshart, S. P. et al. Laboratory mice born to wild mice have natural microbiota and model human immune responses. Science 365, eaaw4361 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ito, R., Takahashi, T., Katano, I. & Ito, M. Current advances in humanized mouse models. Cell Mol. Immunol. 9, 208–214 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • The Complex Trait Consortium The Collaborative Cross, a community resource for the genetic analysis of complex traits. Nat. Genet 36, 1133–1137 (2004).

    Article 

    Google Scholar
     

  • Kitching, A. R. & Ooi, J. D. From bench to pet shop to bedside? The environment and immune function in mice. Kidney Int. 90, 1142–1143 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Medetgul-Ernar, K. & Davis, M. M. Standing on the shoulders of mice. Immunity 55, 1343–1353 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Daly, A. C., Prendergast, M. E., Hughes, A. J. & Burdick, J. A. Bioprinting for the Biologist. Cell 184, 18–32 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Papargyriou, A. et al. Heterogeneity-driven phenotypic plasticity and treatment response in branched-organoid models of pancreatic ductal adenocarcinoma. Nat. Biomed. Eng. https://doi.org/10.1038/s41551-024-01273-9 (2024).

  • Cakir, B. et al. Expression of the transcription factor PU.1 induces the generation of microglia-like cells in human cortical organoids. Nat. Commun. 13, 430 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ogawa, J., Pao, G. M., Shokhirev, M. N. & Verma, I. M. Glioblastoma model using human cerebral organoids. Cell Rep. 23, 1220–1229 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jacob, F. et al. A patient-derived glioblastoma organoid model and biobank recapitulates inter- and intra-tumoral heterogeneity. Cell 180, 188–204.e22 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sachs, N. et al. A Living Biobank of breast cancer organoids captures disease heterogeneity. Cell 172, 373–386.e10 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Dekkers, J. F. et al. Long-term culture, genetic manipulation and xenotransplantation of human normal and breast cancer organoids. Nat. Protoc. 16, 1936–1965 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fujii, M. et al. A colorectal tumor organoid library demonstrates progressive loss of niche factor requirements during tumorigenesis. Cell Stem Cell 18, 827–838 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Drost, J. et al. Sequential cancer mutations in cultured human intestinal stem cells. Nature 521, 43–47 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Steele, N. G. et al. An organoid-based preclinical model of human gastric cancer. Cell. Mol. Gastroenterol. Hepatol. 7, 161–184 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Shah, S. B. et al. Combinatorial treatment rescues tumour-microenvironment-mediated attenuation of MALT1 inhibitors in B-cell lymphomas. Nat. Mater. 22, 511–523 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, S. H. et al. Tumor evolution and drug response in patient-derived organoid models of bladder cancer. Cell 173, 515–528.e17 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, M. R. et al. Organoid morphology-guided classification for oral cancer reveals prognosis. Cell Rep. Medi. 6, 102129 (2025).

  • Pawlowski, K. D., Duffy, J. T., Babak, M. V. & Balyasnikova, I. V. Modeling glioblastoma complexity with organoids for personalized treatments. Trends Mol. Med. 29, 282–296 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yan, H. H. N. et al. A comprehensive human gastric cancer organoid biobank captures tumor subtype heterogeneity and enables therapeutic screening. Cell Stem Cell 23, 882–897.e11 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wagar, L. E. et al. Modeling human adaptive immune responses with tonsil organoids. Nat. Med. 27, 125–135 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhong, Z. et al. Human immune organoids to decode B cell response in healthy donors and patients with lymphoma. Nat. Mater. 24, 297–311 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Griffin, K. H. et al. Engineered bone marrow as a clinically relevant ex vivo model for primary bone cancer research and drug screening. Proc. Natl Acad. Sci. USA 120, e2302101120 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Olijnik, A.-A. et al. Generating human bone marrow organoids for disease modeling and drug discovery. Nat. Protoc. 19, 2117–2146 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gee, K. et al. Spleen organoid units generate functional human and mouse tissue-engineered spleen in a murine model. Tissue Eng. Part A 26, 411–418 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Seet, C. S. et al. Generation of mature T cells from human hematopoietic stem and progenitor cells in artificial thymic organoids. Nat. Methods 14, 521–530 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Recaldin, T. et al. Human organoids with an autologous tissue-resident immune compartment. Nature 633, 165–173 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mallajosyula, V. et al. Coupling antigens from multiple subtypes of influenza can broaden antibody and T cell responses. Science 386, 1389–1395 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wagoner, Z. W. et al. Systems immunology analysis of human immune organoids identifies host-specific correlates of protection to different influenza vaccines. Cell Stem Cell 32, 529–546.e6 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Teufel, C. et al. Lymphoid-tissue-on-chip recapitulates human antibody responses in vitro. https://doi.org/10.1101/2025.01.14.632762 (2025).

  • Morrison, A. I. et al. Integration of lymphatic vasculature to a human lymph node-on-chip enhances physiological immune properties. Mater. Today Bio 35, 102326 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, C. et al. Human airway and nasal organoids reveal escalating replicative fitness of SARS-CoV-2 emerging variants. Proc. Natl Acad. Sci. USA. 120, e2300376120 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wan, Z. et al. Organoid-based neutralization assays reveal a distinctive profile of SARS-CoV-2 antibodies and recapitulate the real-world efficacy. Proc. Natl Acad. Sci. USA. 122, e2509616122 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jain, I., Singh, A. & García, A. J. Microphysiological Systems of Lymphatics and Immune Organs. Adv. Healthcare Mater. e03201 (2025).

  • Yuki, K., Cheng, N., Nakano, M. & Kuo, C. J. Organoid models of tumor immunology. Trends Immunol. 41, 652–664 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rogoz, A., Reis, B. S., Karssemeijer, R. A. & Mucida, D. A 3-D enteroid-based model to study T-cell and epithelial cell interaction. J. Immunol. Methods 421, 89–95 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nozaki, K. et al. Co-culture with intestinal epithelial organoids allows efficient expansion and motility analysis of intraepithelial lymphocytes. J. Gastroenterol. 51, 206–213 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Schreurs, R. R. C. E. et al. Human fetal TNF-α-cytokine-producing CD4+ effector memory T cells promote intestinal development and mediate inflammation early in life. Immunity 50, 462–476.e8 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Collin De l’Hortet, A. et al. Generation of human fatty livers using custom-engineered induced pluripotent stem cells with modifiable SIRT1 metabolism. Cell Metab. 30, 385–401.e9 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Skardal, A. et al. Drug compound screening in single and integrated multi-organoid body-on-a-chip systems. Biofabrication 12, 025017 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Vazquez-Armendariz, A. I. et al. Multilineage murine stem cells generate complex organoids to model distal lung development and disease. EMBO J. 39, e103476 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Schreurs, R. R. C. E., Baumdick, M. E., Drewniak, A. & Bunders, M. J. In vitro co-culture of human intestinal organoids and lamina propria-derived CD4+ T cells. STAR Protoc. 2, 100519 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cattaneo, C. M. et al. Tumor organoid–T-cell coculture systems. Nat. Protoc. 15, 15–39 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Li, K. et al. An organoid co-culture model for probing systemic anti-tumor immunity in lung cancer. Cell Stem Cell 32, 1218–1234.e7 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Neal, J. T. et al. Organoid modeling of the tumor immune microenvironment. Cell 175, 1972–1988.e16 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu, H. et al. A tumor-on-a-chip for in vitro study of CAR-T cell immunotherapy in solid tumors. Nat. Biotechnol. https://doi.org/10.1038/s41587-025-02845-z (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dekkers, J. F. et al. Uncovering the mode of action of engineered T cells in patient cancer organoids. Nat. Biotechnol. 41, 60–69 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Alieva, M. et al. BEHAV3D: a 3D live imaging platform for comprehensive analysis of engineered T cell behavior and tumor response. Nat. Protoc. 19, 2052–2084 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Aw, D., Silva, A. B. & Palmer, D. B. Immunosenescence: emerging challenges for an ageing population. Immunology 120, 435–446 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hossain, M. K., Kim, H.-R. & Chae, H. J. Aging phenotype in AD brain organoids: Track to success and challenges. Ageing Res. Rev. 96, 102256 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Ao, Z. et al. Understanding immune-driven brain aging by human brain organoid microphysiological analysis platform. Adv. Sci. 9, 2200475 (2022).

    Article 

    Google Scholar
     

  • Walrath, T. et al. Age-related changes in intestinal immunity and the microbiome. J. Leukoc. Biol. 109, 1045–1061 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Omrani, O. et al. IFNγ-Stat1 axis drives aging-associated loss of intestinal tissue homeostasis and regeneration. Nat. Commun. 14, 6109 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tao, Y. et al. Aging-like spontaneous epigenetic silencing facilitates wnt activation, stemness, and BrafV600E-Induced tumorigenesis. Cancer Cell 35, 315–328.e6 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Uchida, R. et al. Epigenetic silencing of Lgr5 induces senescence of intestinal epithelial organoids during the process of aging. npj Aging Mech. Dis. 4, 12 (2018).

    Article 
    PubMed Central 

    Google Scholar
     

  • Nalapareddy, K. et al. Canonical Wnt signaling ameliorates aging of intestinal stem cells. Cell Rep. 18, 2608–2621 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kumar, P., Hassan, M., Tacke, F. & Engelmann, C. Delineating the heterogeneity of senescence-induced-functional alterations in hepatocytes. Cell. Mol. Life Sci. 81, 200 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Torrens-Mas, M. et al. Organoids: an emerging tool to study aging signature across human tissues. modeling aging with patient-derived organoids. IJMS 22, 10547 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pitrez, P. R. et al. Cellular reprogramming as a tool to model human aging in a dish. Nat. Commun. 15, 1816 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chini, C. C. S. et al. CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels. Nat. Metab. 2, 1284–1304 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Madl, C. M. Accelerating aging with dynamic biomaterials: recapitulating aged tissue phenotypes in engineered platforms. iScience 26, 106825 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Venkataraman, A. et al. Decoding senescence of aging single cells at the nexus of biomaterials, microfluidics, and spatial omics. npj Aging 10, 57 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Aguado, J. et al. Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology. Nat. Aging 3, 1561–1575 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kong, J. C. H. et al. Tumor-infiltrating lymphocyte function predicts response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. JCO Precision Oncol. 2, 1–15 (2018).

  • Chalabi, M. et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat. Med. 26, 566–576 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jenkins, R. W. et al. Ex vivo profiling of PD-1 Blockade using organotypic tumor spheroids. Cancer Discov. 8, 196–215 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Scognamiglio, G. et al. Patient-derived organoids as a potential model to predict response to PD-1/PD-L1 checkpoint inhibitors. Br. J. Cancer 121, 979–982 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Voabil, P. et al. An ex vivo tumor fragment platform to dissect response to PD-1 blockade in cancer. Nat. Med. 27, 1250–1261 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chakrabarti, J. et al. Hedgehog signaling induces PD-L1 expression and tumor cell proliferation in gastric cancer. Oncotarget 9, 37439–37457 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Deng, J. et al. CDK4/6 inhibition augments antitumor immunity by enhancing T-cell activation. Cancer Discov. 8, 216–233 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sun, Y. et al. Targeting TBK1 to overcome resistance to cancer immunotherapy. Nature 615, 158–167 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhou, Z. et al. A T cell-engaging tumor organoid platform for pancreatic cancer immunotherapy. Adv. Sci. 10, 2300548 (2023).

    Article 
    CAS 

    Google Scholar
     

  • Zhou, R. W. et al. Safe immunosuppression-resistant pan-cancer immunotherapeutics by velcro-like density-dependent targeting of tumor-associated carbohydrate antigens. Cell https://doi.org/10.1016/j.cell.2025.09.001 (2025).

  • Ma, C. et al. Bioengineered immunocompetent preclinical trial-on-chip tool enables screening of CAR T cell therapy for leukaemia. Nat. Biomed. Eng. https://doi.org/10.1038/s41551-025-01428-2 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, C. J. et al. A human liver organoid screening platform for DILI risk prediction. J. Hepatol. 78, 998–1006 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Soussi, F. E. A. et al. Autologous organoid-T cell co-culture platform for modeling of immune-mediated drug-induced liver injury. Adv. Sci. https://doi.org/10.1002/advs.202508584e08584 (2025).

  • Logun, M. et al. Patient-derived glioblastoma organoids as real-time avatars for assessing responses to clinical CAR-T cell therapy. Cell Stem Cell 32, 181–190.e4 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kastenschmidt, J. M. et al. Influenza vaccine format mediates distinct cellular and antibody responses in human immune organoids. Immunity 56, 1910–1926.e7 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yin, Q. et al. A TLR7-nanoparticle adjuvant promotes a broad immune response against heterologous strains of influenza and SARS-CoV-2. Nat. Mater. 22, 380–390 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Demmers, L. C. et al. Single-cell derived tumor organoids display diversity in HLA class I peptide presentation. Nat. Commun. 11, 5338 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dost, A. F. M. et al. Organoids model transcriptional hallmarks of oncogenic KRAS activation in lung epithelial progenitor cells. Cell Stem Cell 27, 663–678.e8 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Maru, Y. et al. Kras activation in endometrial organoids drives cellular transformation and epithelial-mesenchymal transition. Oncogenesis 10, 46 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Miura, A. et al. Oncogenic potential of human pluripotent stem cell-derived lung organoids with HER2 overexpression. Int. J. Cancer 149, 1593–1604 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Toth, A. et al. Alveolar epithelial progenitor cells require Nkx2-1 to maintain progenitor-specific epigenomic state during lung homeostasis and regeneration. Nat. Commun. 14, 8452 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Reza, H. A. et al. Multi-zonal liver organoids from human pluripotent stem cells. Nature https://doi.org/10.1038/s41586-025-08850-1 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Frenkel, N. et al. Long-lived human lymphatic endothelial cells to study lymphatic biology and lymphatic vessel/tumor coculture in a 3D microfluidic model. ACS Biomater. Sci. Eng. 7, 3030–3042 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Votanopoulos, K. I. et al. Model of patient-specific immune-enhanced organoids for immunotherapy screening: feasibility study. Ann. Surg. Oncol. 27, 1956–1967 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Ronaldson-Bouchard, K. et al. A multi-organ chip with matured tissue niches linked by vascular flow. Nat. Biomed. Eng. 6, 351–371 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Adu-Berchie, K. et al. Generation of functionally distinct T-cell populations by altering the viscoelasticity of their extracellular matrix. Nat. Biomed. Eng. 7, 1374–1391 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • LeSavage, B. L. et al. Engineered matrices reveal stiffness-mediated chemoresistance in patient-derived pancreatic cancer organoids. Nat. Mater. 23, 1138–1149 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ballerini, M. et al. A gut-on-a-chip incorporating human faecal samples and peristalsis predicts responses to immune checkpoint inhibitors for melanoma. Nat. Biomed. Eng. https://doi.org/10.1038/s41551-024-01318-z (2025).

  • Etesami, N. S. et al. B cells in the pneumococcus-infected lung are heterogeneous and require CD4+ T cell help including CD40L to become resident memory B cells. Front. Immunol. 15, 1382638 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lawlor, K. T. et al. Cellular extrusion bioprinting improves kidney organoid reproducibility and conformation. Nat. Mater. 20, 260–271 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bliley, J. M., Shiwarski, D. J. & Feinberg, A. W. 3D-bioprinted human tissue and the path toward clinical translation. Sci. Transl. Med. 14, eabo7047 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Schuster, B. et al. Automated microfluidic platform for dynamic and combinatorial drug screening of tumor organoids. Nat. Commun. 11, 5271 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Choi, D. et al. Microfluidic organoid cultures derived from pancreatic cancer biopsies for personalized testing of chemotherapy and immunotherapy. Adv. Sci. 11, 2303088 (2024).

    Article 
    CAS 

    Google Scholar
     

  • Xue, X. et al. Generation of spatially patterned human neural tube-like structures using microfluidic gradient devices. Nat. Protoc. https://doi.org/10.1038/s41596-025-01266-1 (2025).

    Article 
    PubMed 

    Google Scholar
     

  • Lehrich, B. M. et al. Precision targeting of β-catenin induces tumor reprogramming and immunity in hepatocellular cancers. Nat. Commun. 16, 5009 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Deglincerti, A. et al. Self-organization of human embryonic stem cells on micropatterns. Nat. Protoc. 11, 2223–2232 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Velasco, V., Shariati, S. A. & Esfandyarpour, R. Microtechnology-based methods for organoid models. Microsyst. Nanoeng. 6, 76 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Betjes, M. A., Kok, R. N. U., Tans, S. J. & Van Zon, J. S. Cell tracking with accurate error prediction. Nat. Methods https://doi.org/10.1038/s41592-025-02845-6 (2025).

  • Johnson, J. A. I. et al. Human interpretable grammar encodes multicellular systems biology models to democratize virtual cell laboratories. Cell 188, 4711–4733.e37 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kok, R. N. U., Spoelstra, W. K., Betjes, M. A., Van Zon, J. S. & Tans, S. J. Label-free cell imaging and tracking in 3D organoids. Cell Rep. Phys. Sci. 6, 102522 (2025).

    Article 

    Google Scholar
     

  • Hu, M. et al. SPACE: spatially resolved multiomic analysis for high-throughput CRISPR screening in 3D models. https://doi.org/10.1101/2025.09.14.675819 (2025).

  • Diosdi, A. et al. HCS-3DX, a next-generation AI-driven automated 3D-oid high-content screening system. Nat. Commun. 16, 8897 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • He, Z. et al. An integrated transcriptomic cell atlas of human neural organoids. Nature 635, 690–698 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Xu, Q. et al. An integrated transcriptomic cell atlas of human endoderm-derived organoids. Nat. Genet. https://doi.org/10.1038/s41588-025-02182-6 (2025).

  • Kong, J. et al. Network-based machine learning in colorectal and bladder organoid models predicts anti-cancer drug efficacy in patients. Nat. Commun. 11, 5485 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kong, J. et al. Network-based machine learning approach to predict immunotherapy response in cancer patients. Nat. Commun. 13, 3703 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cai, H. et al. Brain organoid reservoir computing for artificial intelligence. Nat. Electron 6, 1032–1039 (2023).

    Article 

    Google Scholar
     

  • Bjornson-Hooper, Z. B. et al. A comprehensive atlas of immunological differences between humans, mice, and non-human primates. Front. Immunol. 13, 867015 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Huminiecki, L. & Wolfe, K. H. Divergence of spatial gene expression profiles following species-specific gene duplications in human and mouse. Genome Res. 14, 1870–1879 (2004).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu, T. et al. Cross-species single-cell transcriptomic analysis reveals pre-gastrulation developmental differences among pigs, monkeys, and humans. Cell Discov. 7, 8 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar