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  3. A tumor-on-a-chip for in vitro study of CAR-T cell immunotherapy in solid tumors

A tumor-on-a-chip for in vitro study of CAR-T cell immunotherapy in solid tumors

  • Nat Biotechnol. 2025 Oct 17. doi: 10.1038/s41587-025-02845-z.
Haijiao Liu 1 2,  Estela Noguera-Ortega 3,  Xuanqi Dong 1,  Won Dong Lee 4 5 6,  Jeehan Chang 1 2,  Sezin Aday Aydin 1,  Yumei Li 7,  Yonghee Shin 8 9,  Xinyi Shi 3,  Maria Liousia 3,  Marina C Martinez 3,  Joshua J Brotman 3,  Soyeon Kim 3,  Zeyu Chen 10 11,  Anni Wang 1,  Zirui Ou 1,  Jungwook Paek 1,  Ju Young Park 1,  Aidi Liu 1,  Haonan Hu 1,  Zebin Xiao 12,  Dora Maria Racca 1,  Se-Jeong Kim 1,  G Scott Worthen 13,  Wei Guo 7,  Ellen Puré 10 12 14,  Taewook Kang 8,  Joshua D Rabinowitz 4 5,  E John Wherry 10 11,  Edmund K Moon 3,  Steven M Albelda 3,  Dan Dongeun Huh 15 16 17
Affiliations

Affiliations

  • 1 Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
  • 2 NSF Science and Technology Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA, USA.
  • 3 Pulmonary, Allergy and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 4 Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
  • 5 Department of Chemistry, Princeton University, Princeton, NJ, USA.
  • 6 Department of Biochemistry, Yonsei University, Seoul, Republic of Korea.
  • 7 Department of Biology, University of Pennsylvania, Philadelphia, PA, USA.
  • 8 Department of Chemical and Biomolecular Engineering, Sogang University, Seoul, Republic of Korea.
  • 9 Department of Biologics, Gachon University, Incheon, Republic of Korea.
  • 10 Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 11 Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 12 Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 13 Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 14 Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 15 Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA. huhd@seas.upenn.edu.
  • 16 NSF Science and Technology Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA, USA. huhd@seas.upenn.edu.
  • 17 Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. huhd@seas.upenn.edu.
PMID: 41107533 DOI: 10.1038/s41587-025-02845-z
Abstract

Our limited understanding of cancer-immune interactions remains a critical barrier to advancing chimeric antigen receptor (CAR)-T cell therapy for solid malignancies. Here, we present a microengineered system that enables vascularization of human tumor explants and their controlled perfusion with immune cells to model the activity of CAR-T cells in the tumor microenvironment. Using vascularized human lung adenocarcinoma tumors, we first demonstrate the ability of our tumor-on-a-chip system to simulate, visualize and interrogate CAR-T cell function. We then test a chemokine-directed CAR-T cell engineering strategy in a model of malignant pleural mesothelioma and validate our findings in a matching in vivo mouse model. Finally, we describe a potential therapeutic target that can be pharmacologically modulated to increase the efficacy of CAR-T cells in lung adenocarcinoma, for which we present biomarkers identified by global metabolomics analysis. Our microphysiological system provides promising in vitro technology to advance the development of adoptive cell therapies for Cancer and Other Diseases.

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