A study from the FLI, identifies a mechanism by which tumors exclude immune cells and shows how intermittent YAP/TAZ inhibition can help restore the immune response. The work was also recognized with a Poster Prize at the Frankfurt Cancer Conference 2026.
JENA, Germany. How does an aggressive tumor evade attack by the immune system? And, more importantly, can the tumor microenvironment be modified to make the tumor accessible to immune cells again?
A study conducted by the Transcriptional Control of Tissue Homeostasis research group, led by PD Dr. Björn von Eyss at the Leibniz Institute on Aging – Fritz Lipmann Institute (FLI) in Jena, provides new insights into these questions in the context of cholangiocarcinoma, an aggressive cancer of the bile ducts.
The research, with Dr. Marco Jessen as first author, was published on July 2, 2026, in the Journal of Clinical Investigation with the title “Extracellular matrix reprogramming by the YAP/TAZ–TGF-β2 axis drives immune exclusion in cholangiocarcinoma models.” The findings identify a mechanism involving YAP/TAZ and the signaling molecule TGF-β2 that contributes to remodeling the tumor microenvironment and preventing T cells from effectively penetrating the tumor. The study further shows that temporary modulation of YAP/TAZ can promote immune-cell infiltration and, in combination with immunotherapy, enhance the antitumor response in experimental models.
When Tumors Become Inaccessible to the Immune System
Cholangiocarcinoma is characterized by a complex tumor microenvironment in which the extracellular matrix (ECM) plays a key role. This network of proteins and other molecules normally provides structural support to tissues but can become extensively remodeled in tumors.
As a result, the dense tissue surrounding the tumor cells acts as a physical and chemical barrier that restricts T-cell infiltration. Although T cells may be capable of recognizing and attacking tumor cells, they are unable to reach them in sufficient numbers—a major driver of resistance to immunotherapy. The FLI study identifies the YAP/TAZ–TGF-β2 axis as a primary driver of this process. In cholangiocarcinoma, the activity of the transcription co-activators YAP and TAZ helps maintain a desmoplastic microenvironment that shields the tumor from immune attack.
“The dense tissue surrounding the tumor cells can make it difficult for T cells to reach them. Our results show that YAP and TAZ, partly through a molecule called TGF-β2, help maintain this environment,” explains Dr. Marco Jessen, first author of the study.
Making the Tumor Accessible Again
YAP and TAZ also perform essential functions in healthy tissues, which means that prolonged, systemic inhibition of these regulators leads to significant adverse effects. To overcome this, the researchers investigated an alternative approach: intermittent, or “pulsed,” inhibition of YAP/TAZ.
To evaluate both therapeutic efficacy and possible side effects, the team utilized a mouse model in which YAP and TAZ can be switched off in adult tissues. Tumors were generated using hydrodynamic tail vein injection a technique that delivers DNA carrying cancer-driving genes to liver cells. In this study, activated AKT and Notch intracellular domain (NICD) were used to induce cholangiocarcinoma.
“When we switch off YAP and TAZ, the tumor tissue changes and more T cells can enter. However, entering the tumor is only the first challenge,” says Jessen. “The T cells must also remain active enough to kill cancer cells. Tumors can exploit the immune system’s natural ‘checkpoints’, which normally prevent immune cells from attacking healthy tissue. In our mouse model, the T cells that entered the tumor showed signs of exhaustion, meaning they started to express these checkpoint markers.”
To counteract this, the researchers combined YAP/TAZ inhibition with an immune checkpoint blockade (ICB) using an antibody against PD-1 one of the primary checkpoints that restrict T-cell activity. In the experimental models, this combination successfully reversed T-cell exhaustion, restored sensitivity to immunotherapy, and significantly reduced tumor growth.
From Discovery to International Recognition
Following its publication in the Journal of Clinical Investigation, the findings were presented by Marco Jessen at the Frankfurt Cancer Conference 2026 (September 2–4), where his presentation was awarded a Poster Prize.
Towards New Therapeutic Strategies
The study highlights that improving access of immune cells to the tumor and maintaining an effective T-cell response are closely interconnected. Combining temporary modulation of the tumor microenvironment with immunotherapy could therefore represent a potential strategy to overcome treatment resistance. At the same time, the findings were obtained in experimental models of cholangiocarcinoma, and further research is needed to determine how these results could translate to patients.
“The most important question now is whether the effects we observed in mice can also be achieved in patients with cholangiocarcinoma,” concludes Dr. Marco Jessen. “We need to find out which patients might benefit, how long YAP/TAZ should be inhibited, and whether combining this approach with immune checkpoint inhibitors is both effective and safe.”
Publication
Extracellular matrix reprogramming by the YAP/TAZ/TGF-β2 axis drives immune exclusion in cholangiocarcinoma models. Marco Jessen, KyungMok Kim, Marie Tollot-Wegner, Anita Cindric Vranesic, Cagla Dönmez, Celina Junker, Tina Lehmann, Aditiya Khandelwal, Yuliya Kurlishchuk, Tom Hünniger, Christin Ritter, Evaristo Di Napoli, Shyam Krishnan Murali, Konrad Bücking, Viktoria Haug, Sabine Muth, Tracy T. Tang, Andreas Rosenwald, Markus Radsak, Donato Inverso, Tanja Deckert-Gaudig, Volker Deckert, Orlando Paciello, Björn von Eyss. The Journal of Clinical Investigation (JCL). July 2, 2026 doi: 10.1172/JCI201579.
https://www.jci.org/articles/view/201579
