Adoptive T-cell therapies—in which T-cells are re-engineered outside the body to recognize dangerous cells and then infused back into the body to go on the attack—are on the frontier of medicine.
One such approach—using chimeric antigen receptor (CAR) T cells—has demonstrated remarkable efficacy in treating liquid tumors (which form in blood, lymphatic fluids, or bone marrow), with many patients achieving tumor reduction or long-term remission.
However, this approach has yielded much more disappointing results in the solid tumors that account for most cancers, with response rates below 25%. No one has known why.
Ryan Notti, Ph.D., a special fellow in the Department of Medicine at Memorial Sloan Kettering Cancer Center and an instructor of clinical investigation in the Laboratory of Molecular Electron Microscopy at Rockefeller University, teamed up with Professor Thomas Walz, Ph.D., a world expert in cryo-EM imaging, to see whether clues might lie in the T-cell receptor’s fundamental structure.
Essential new characteristics of T-cell receptors
As reported in the December 16, 2025, edition of Nature Communications, the researchers used cryo-EM to identify characteristics of the T-cell receptor (TCR)—essential to a variety of T-cell therapies—that had not been observed before. [1]*
“All the data we’d read depicted TCR as being open and extended in its dormant state, but we found that before activation, it has a compacted, closed shape,” Notti said.
“After binding to an antigen, it sort of springs open like a jack-in-the-box,” he added.
This work was made possible in part by Rockefeller’s Clinical Scholars Program, a three-year program designed for clinically trained medical professionals to receive laboratory research training and learn the fundamentals of translational research, which is accredited by the New England Commission of Higher Education (NECHE; formerly the Commission on Institutions of Higher Education of the New England Association of Schools and Colleges, Inc.). Most graduates of this program are physician-scientists like Notti who work at the intersection of medical practice and laboratory research, bringing insights from patient care to the lab and vice versa.
We spoke with Notti and Walz about the translational potential of this partnership between clinical insight and basic research, ranging from new cancer treatments to improved vaccine design.
How did this line of research develop?
Ryan Notti: I initially had the idea when I was doing my medical residency in 2018. One key question I was interested in was how these T-cell therapies work at the molecular level, and I couldn’t obtain a clear answer regarding how a TCR or a CAR is activated.
Also, these therapies don’t work for most cancers, and understanding exactly why that is and how to address it isn’t easy without a fundamental understanding of how these biological machines work. I earned my Ph.D. in structural microbiology from Rockefeller in 2015, so I thought that basic research on the T-cell receptor’s structure, particularly in a membrane environment, could provide this knowledge. That dovetailed nicely with my enrollment in the Clinical Scholars program here, which I joined to deepen my understanding of translational science and secure protected research time.
Also, Tom is a luminary in the field of electron microscopy—especially when it comes to imaging challenging membrane proteins—so when he said he was interested in the project, I was thrilled.
Thomas Walz: When Ryan suggested it, I was thrilled as well. It’s very rare to have a medical doctor who is interested in structure, and the project was right in line with my lab’s basic research on membrane proteins. The TCR is embedded in the T-cell membrane, and my group specializes in studying membrane proteins in custom-designed membrane environments. We can vary parameters such as membrane thickness and size, and then observe how proteins respond using cryo-EM.
I also thought it was a great project because it shows the strengths of both basic research and its translation. Greater knowledge of almost any protein will eventually have biomedical applications.
And what did your work reveal about the process of T cell activation?
RN: How it gets activated has been a major debate for 40 years—ever since the T cell receptor was first discovered—and whether it undergoes a shape change as a result. We found that it does, which helps explain how information moves from outside the cell, where antigens such as infectious agents or proteins from a malignancy are presented to the receptor, to the inside of the cell, where the signaling that activates the T cell occurs.
TW: That the basis of T-cell signaling has remained so controversial until our work is quite remarkable. Further foundational discoveries about the TCR are to come. In this paper, we published two of TCR’s conformational states, but Ryan has already imaged many, many more.
What are the health implications of your findings?
RN: For one thing, we anticipate that this work will help re-engineer receptor-based and cell-based cancer therapies. For example, my clinical specialty is sarcomas—cancers that arise from soft tissue or bone—and adoptive T-cell therapy has been used successfully for certain very rare sarcomas. These insights may help fine-tune receptor sensitivity to improve the effectiveness of this approach across a broader range of sarcomas.
It also may help improve vaccine design. Folks in the field can use our structures to see which types of antigens might be better or worse at activating the TCR, and whether these different modes of interaction have implications for how the receptor functions.
Understanding how the TCR responds to foreign antigens is essential for vaccine design because T-cells signal to B cells, which produce antibodies. Getting T-cells and B-cells to communicate is an integral part of making an effective vaccine.
More generally, our study is a strong example of how basic science is essential for accelerating improvements in clinical practice.
TW: Yes, exactly. If no one is pursuing the kind of basic research we conduct at Rockefeller, there will be nothing to translate in the future.
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Note: * Also see: The Cutting Edge of Cancer Treatment: T-cell Receptors May Improve Cancer Immunotherapies [Link]
Reference
[1] Notti RQ, Yi F, Heissel S, Bush MW, Molvi Z, Das P, Molina H, Klebanoff CA, Walz T. The resting and ligand-bound states of the membrane-embedded human T-cell receptor-CD3 complex. Nat Commun 16, 10996 (2025). https://doi.org/10.1038/s41467-025-66939-7
Featured image: Ryan Notti, Ph.d. (left) and Thomas Walz, Ph.D. (right) have discovered new characteristics of a T-cell receptor that are essential to a variety of cutting-edge T-cell immunotherapies. © 2025 The Rockefeller University. Used with permission.
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