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ResearchIn-Press PreviewHepatologyOncology Open Access | 10.1172/JCI201579

Extracellular matrix reprogramming by the YAP/TAZ– TGF-ß2 axis drives immune exclusion in cholangiocarcinoma models

Marco Jessen,1 KyungMok Kim,1 Marie Tollot-Wegner,1 Anita Cindric Vranesic,1 Cagla Dönmez,1 Celina Junker,1 Tina Lehmann,1 Advitiya Khandelwal,1 Yuliya Kurlishchuk,1 Tom Hünniger,1 Christin Ritter,1 Evaristo Di Napoli,2 Shyam Murali,1 Konrad Bücking,1 Viktoria Haug,3 Sabine Muth,4 Tracy T. Tang,5 Andreas Rosenwald,3 Markus Radsak,6 Donato Inverso,7 Tanja Deckert-Gaudig,8 Volker Deckert,8 Orlando Paciello,2 and Björn von Eyss1

1Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V. (FLI), Jena, Germany

2Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy

3Institute of Pathology, University of Würzburg, Würzburg, Germany

4nstitute of Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

5Vivace Therapeutics, Inc., San Mateo, United States of America

6Department of Hematology and Oncology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

7Vascular Pathobiology Unit, Vita-Salute San Raffaele University, Milan, Italy

8Leibniz Institute of Photonic Technology, Jena, Germany

Find articles by Jessen, M. in: PubMed | Google Scholar |

1Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V. (FLI), Jena, Germany

2Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy

3Institute of Pathology, University of Würzburg, Würzburg, Germany

4nstitute of Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

5Vivace Therapeutics, Inc., San Mateo, United States of America

6Department of Hematology and Oncology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

7Vascular Pathobiology Unit, Vita-Salute San Raffaele University, Milan, Italy

8Leibniz Institute of Photonic Technology, Jena, Germany

Find articles by Kim, K. in: PubMed | Google Scholar

1Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V. (FLI), Jena, Germany

2Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy

3Institute of Pathology, University of Würzburg, Würzburg, Germany

4nstitute of Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

5Vivace Therapeutics, Inc., San Mateo, United States of America

6Department of Hematology and Oncology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

7Vascular Pathobiology Unit, Vita-Salute San Raffaele University, Milan, Italy

8Leibniz Institute of Photonic Technology, Jena, Germany

Find articles by Tollot-Wegner, M. in: PubMed | Google Scholar

1Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V. (FLI), Jena, Germany

2Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy

3Institute of Pathology, University of Würzburg, Würzburg, Germany

4nstitute of Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

5Vivace Therapeutics, Inc., San Mateo, United States of America

6Department of Hematology and Oncology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

7Vascular Pathobiology Unit, Vita-Salute San Raffaele University, Milan, Italy

8Leibniz Institute of Photonic Technology, Jena, Germany

Find articles by Cindric Vranesic, A. in: PubMed | Google Scholar

1Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V. (FLI), Jena, Germany

2Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy

3Institute of Pathology, University of Würzburg, Würzburg, Germany

4nstitute of Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

5Vivace Therapeutics, Inc., San Mateo, United States of America

6Department of Hematology and Oncology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

7Vascular Pathobiology Unit, Vita-Salute San Raffaele University, Milan, Italy

8Leibniz Institute of Photonic Technology, Jena, Germany

Find articles by Dönmez, C. in: PubMed | Google Scholar

1Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V. (FLI), Jena, Germany

2Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy

3Institute of Pathology, University of Würzburg, Würzburg, Germany

4nstitute of Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

5Vivace Therapeutics, Inc., San Mateo, United States of America

6Department of Hematology and Oncology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

7Vascular Pathobiology Unit, Vita-Salute San Raffaele University, Milan, Italy

8Leibniz Institute of Photonic Technology, Jena, Germany

Find articles by Junker, C. in: PubMed | Google Scholar

1Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V. (FLI), Jena, Germany

2Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy

3Institute of Pathology, University of Würzburg, Würzburg, Germany

4nstitute of Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

5Vivace Therapeutics, Inc., San Mateo, United States of America

6Department of Hematology and Oncology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

7Vascular Pathobiology Unit, Vita-Salute San Raffaele University, Milan, Italy

8Leibniz Institute of Photonic Technology, Jena, Germany

Find articles by Lehmann, T. in: PubMed | Google Scholar

1Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V. (FLI), Jena, Germany

2Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy

3Institute of Pathology, University of Würzburg, Würzburg, Germany

4nstitute of Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

5Vivace Therapeutics, Inc., San Mateo, United States of America

6Department of Hematology and Oncology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

7Vascular Pathobiology Unit, Vita-Salute San Raffaele University, Milan, Italy

8Leibniz Institute of Photonic Technology, Jena, Germany

Find articles by Khandelwal, A. in: PubMed | Google Scholar

1Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V. (FLI), Jena, Germany

2Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy

3Institute of Pathology, University of Würzburg, Würzburg, Germany

4nstitute of Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

5Vivace Therapeutics, Inc., San Mateo, United States of America

6Department of Hematology and Oncology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

7Vascular Pathobiology Unit, Vita-Salute San Raffaele University, Milan, Italy

8Leibniz Institute of Photonic Technology, Jena, Germany

Find articles by Kurlishchuk, Y. in: PubMed | Google Scholar

1Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V. (FLI), Jena, Germany

2Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy

3Institute of Pathology, University of Würzburg, Würzburg, Germany

4nstitute of Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

5Vivace Therapeutics, Inc., San Mateo, United States of America

6Department of Hematology and Oncology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

7Vascular Pathobiology Unit, Vita-Salute San Raffaele University, Milan, Italy

8Leibniz Institute of Photonic Technology, Jena, Germany

Find articles by Hünniger, T. in: PubMed | Google Scholar

1Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V. (FLI), Jena, Germany

2Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy

3Institute of Pathology, University of Würzburg, Würzburg, Germany

4nstitute of Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

5Vivace Therapeutics, Inc., San Mateo, United States of America

6Department of Hematology and Oncology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

7Vascular Pathobiology Unit, Vita-Salute San Raffaele University, Milan, Italy

8Leibniz Institute of Photonic Technology, Jena, Germany

Find articles by Ritter, C. in: PubMed | Google Scholar

1Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V. (FLI), Jena, Germany

2Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy

3Institute of Pathology, University of Würzburg, Würzburg, Germany

4nstitute of Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

5Vivace Therapeutics, Inc., San Mateo, United States of America

6Department of Hematology and Oncology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

7Vascular Pathobiology Unit, Vita-Salute San Raffaele University, Milan, Italy

8Leibniz Institute of Photonic Technology, Jena, Germany

Find articles by Di Napoli, E. in: PubMed | Google Scholar

1Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V. (FLI), Jena, Germany

2Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy

3Institute of Pathology, University of Würzburg, Würzburg, Germany

4nstitute of Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

5Vivace Therapeutics, Inc., San Mateo, United States of America

6Department of Hematology and Oncology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

7Vascular Pathobiology Unit, Vita-Salute San Raffaele University, Milan, Italy

8Leibniz Institute of Photonic Technology, Jena, Germany

Find articles by Murali, S. in: PubMed | Google Scholar

1Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V. (FLI), Jena, Germany

2Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy

3Institute of Pathology, University of Würzburg, Würzburg, Germany

4nstitute of Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

5Vivace Therapeutics, Inc., San Mateo, United States of America

6Department of Hematology and Oncology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

7Vascular Pathobiology Unit, Vita-Salute San Raffaele University, Milan, Italy

8Leibniz Institute of Photonic Technology, Jena, Germany

Find articles by Bücking, K. in: PubMed | Google Scholar

1Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V. (FLI), Jena, Germany

2Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy

3Institute of Pathology, University of Würzburg, Würzburg, Germany

4nstitute of Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

5Vivace Therapeutics, Inc., San Mateo, United States of America

6Department of Hematology and Oncology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

7Vascular Pathobiology Unit, Vita-Salute San Raffaele University, Milan, Italy

8Leibniz Institute of Photonic Technology, Jena, Germany

Find articles by Haug, V. in: PubMed | Google Scholar

1Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V. (FLI), Jena, Germany

2Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy

3Institute of Pathology, University of Würzburg, Würzburg, Germany

4nstitute of Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

5Vivace Therapeutics, Inc., San Mateo, United States of America

6Department of Hematology and Oncology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

7Vascular Pathobiology Unit, Vita-Salute San Raffaele University, Milan, Italy

8Leibniz Institute of Photonic Technology, Jena, Germany

Find articles by Muth, S. in: PubMed | Google Scholar

1Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V. (FLI), Jena, Germany

2Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy

3Institute of Pathology, University of Würzburg, Würzburg, Germany

4nstitute of Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

5Vivace Therapeutics, Inc., San Mateo, United States of America

6Department of Hematology and Oncology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

7Vascular Pathobiology Unit, Vita-Salute San Raffaele University, Milan, Italy

8Leibniz Institute of Photonic Technology, Jena, Germany

Find articles by Tang, T. in: PubMed | Google Scholar

1Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V. (FLI), Jena, Germany

2Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy

3Institute of Pathology, University of Würzburg, Würzburg, Germany

4nstitute of Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

5Vivace Therapeutics, Inc., San Mateo, United States of America

6Department of Hematology and Oncology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

7Vascular Pathobiology Unit, Vita-Salute San Raffaele University, Milan, Italy

8Leibniz Institute of Photonic Technology, Jena, Germany

Find articles by Rosenwald, A. in: PubMed | Google Scholar

1Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V. (FLI), Jena, Germany

2Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy

3Institute of Pathology, University of Würzburg, Würzburg, Germany

4nstitute of Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

5Vivace Therapeutics, Inc., San Mateo, United States of America

6Department of Hematology and Oncology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

7Vascular Pathobiology Unit, Vita-Salute San Raffaele University, Milan, Italy

8Leibniz Institute of Photonic Technology, Jena, Germany

Find articles by Radsak, M. in: PubMed | Google Scholar

1Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V. (FLI), Jena, Germany

2Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy

3Institute of Pathology, University of Würzburg, Würzburg, Germany

4nstitute of Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

5Vivace Therapeutics, Inc., San Mateo, United States of America

6Department of Hematology and Oncology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

7Vascular Pathobiology Unit, Vita-Salute San Raffaele University, Milan, Italy

8Leibniz Institute of Photonic Technology, Jena, Germany

Find articles by Inverso, D. in: PubMed | Google Scholar |

1Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V. (FLI), Jena, Germany

2Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy

3Institute of Pathology, University of Würzburg, Würzburg, Germany

4nstitute of Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

5Vivace Therapeutics, Inc., San Mateo, United States of America

6Department of Hematology and Oncology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

7Vascular Pathobiology Unit, Vita-Salute San Raffaele University, Milan, Italy

8Leibniz Institute of Photonic Technology, Jena, Germany

Find articles by Deckert-Gaudig, T. in: PubMed | Google Scholar

1Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V. (FLI), Jena, Germany

2Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy

3Institute of Pathology, University of Würzburg, Würzburg, Germany

4nstitute of Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

5Vivace Therapeutics, Inc., San Mateo, United States of America

6Department of Hematology and Oncology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

7Vascular Pathobiology Unit, Vita-Salute San Raffaele University, Milan, Italy

8Leibniz Institute of Photonic Technology, Jena, Germany

Find articles by Deckert, V. in: PubMed | Google Scholar

1Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V. (FLI), Jena, Germany

2Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy

3Institute of Pathology, University of Würzburg, Würzburg, Germany

4nstitute of Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

5Vivace Therapeutics, Inc., San Mateo, United States of America

6Department of Hematology and Oncology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

7Vascular Pathobiology Unit, Vita-Salute San Raffaele University, Milan, Italy

8Leibniz Institute of Photonic Technology, Jena, Germany

Find articles by Paciello, O. in: PubMed | Google Scholar

1Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V. (FLI), Jena, Germany

2Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy

3Institute of Pathology, University of Würzburg, Würzburg, Germany

4nstitute of Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

5Vivace Therapeutics, Inc., San Mateo, United States of America

6Department of Hematology and Oncology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

7Vascular Pathobiology Unit, Vita-Salute San Raffaele University, Milan, Italy

8Leibniz Institute of Photonic Technology, Jena, Germany

Find articles by von Eyss, B. in: PubMed | Google Scholar

Published July 2, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI201579.
Copyright © 2026, Jessen et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 2, 2026 - Version history
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Abstract

YAP and TAZ, key effectors of the Hippo pathway, are often hyperactivated in cancer, promoting tumor progression and therapy resistance. Their oncogenic role depends on interaction with TEAD transcription factors, making the TEAD-YAP/TAZ complex a promising therapeutic target. Using translational mouse models, we showed here that sustained systemic YAP/TAZ depletion caused severe side effects. These could be avoided through pulsed inhibition, which effectively suppressed tumor growth, even at advanced stages. We identified Tgfb2 as a critical YAP/TAZ target gene for tumor formation and demonstrated that YAP/TAZ drove T cell exclusion via activation of tissue remodeling genes. Consequently, YAP/TAZ inhibition enhanced immune cell infiltration. However, infiltrating T cells rapidly underwent exhaustion. Combining YAP/TAZ inhibition with immune checkpoint blockade (ICB) reversed this exhaustion and sensitized resistant tumors to immunotherapy. This combination reshaped the tumor microenvironment to support immune cell infiltration and activation, representing a therapeutic strategy that maximizes anti-tumor immunity while minimizing toxicity.

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