UCLA and Stanford Medicine researchers, in collaboration with scientists from the University of Utah and Columbia University, have engineered a new class of supercharged T cells that are stronger, longer-lasting, and more precise at killing prostate cancer cells by fine-tuning how they physically interact with tumor cells.
Instead of simply making T cell receptors bind more tightly to cancer, the team, collaborating within the network of the Parker Institute of Cancer Immunotherapy (PICI), introduced a natural "catch bond," a fishhook-like interaction that strengthens when cells pull against each other. This allows T cells to latch onto cancer cells more effectively at the moment they attack, helping them recognize the tumor, stay engaged longer and deliver a more powerful and targeted immune response without damaging healthy tissue.
The approach, described in the journal Science, represents an important step toward developing safer, more effective T cell therapies for prostate cancer and could potentially be adapted to treat a wide range of other tumors.
"In our collaborative work, we demonstrate that just a single amino acid change introducing these 'fishhooks' is sufficient to transform immune cells into a potent killer mode," said study co-senior author Dr. K. Christopher Garcia, the Younger Family Professor and Professor of Structural Biology at the Stanford School of Medicine and a Howard Hughes Medical Institute (HHMI) investigator.
"By engineering catch bonds, we aim to benefit more patients by overcoming immune tolerance," said co-senior author Dr. Owen N. Witte , who holds the Presidential Chair in Developmental Immunology in the Department of Microbiology, Immunology, and Molecular Genetics and is a member of the UCLA Health Jonsson Comprehensive Cancer Center (JCCC).
Both Garcia and Witte are investigators at PICI, where they are pioneering the development of next-generation cancer immunotherapies.
Why it matters
T cells are a powerful weapon in the fight against cancer, forming the basis of treatments such as CAR-T cell therapy and checkpoint inhibitors. This research centers on another type of immunotherapy approach called T cell receptor (TCR) therapy, which engineers T cells to recognize specific proteins on cancer cells, allowing for highly targeted attacks.
Many of these proteins, however, are "self-antigens," or molecules normally found in the body. To prevent these T cells from attacking healthy tissue, the immune system naturally eliminates the strongest cancer-fighting T cells during development. This leaves behind weaker T cell receptors that may struggle to recognize and destroy tumors, particularly those that have learned to evade immune defenses.
What the study did
To overcome this challenge, researchers from UCLA and Stanford Medicine focused on fine-tuning naturally occurring T cell receptors to strengthen their ability to recognize a common prostate cancer protein called prostatic acid phosphatase (PAP), which is commonly expressed on prostate tissue and prostate tumors. The team identified a naturally weak TCR, known as TCR156, that could detect PAP but was not strong enough to effectively kill cancer cells.
Using a novel technique called catch bond engineering, a concept developed by the Garcia Lab at Stanford Medicine, the researchers "turbocharged" the T cells. In the body, T cells form brief, mechanical bonds with their targets, known as catch bonds, which help them sense and respond to threats. By altering just one or two amino acids in the T cell receptor, the scientists were able to strengthen these bonds while preserving the T cells' natural ability to recognize their specific target.
Multiple engineered versions of TCR156 were created and tested. Two candidates proved to be the most effective. These engineered T cells were analyzed for their ability to recognize tumors, release cancer-killing molecules, proliferate, and resist exhaustion. Advanced imaging, single-cell RNA sequencing, and structural analyses were used to confirm that the modifications improved T cell function while maintaining precision and avoiding off-target effects.
Structural and computer modeling studies showed that the catch bond mutations did not change the overall TCR shape but primed it to form a new interaction with PAP when the T cell engaged the tumor, explaining how the engineered T cells could remain highly specific while dramatically boosting their cancer-killing ability.
What they found
The researchers found that a single amino acid change created a catch bond hotspot that significantly enhanced T cell function. This change did not directly contact the cancer protein until the T cell engaged dynamically, demonstrating that a tiny modification can have a major effect. Most importantly, the modifications did not make the cells attack healthy tissue.
The strength and lifetime of the TCR's bond with PAP under force were better predictors of tumor-killing ability than traditional measures of binding strength. In laboratory experiments, the engineered T cells showed longer contact with cancer cells, greater secretion of tumor-killing molecules such as Granzyme B, IFNγ, and TNFα, and improved proliferation while resisting exhaustion.
In mouse models, the engineered T cells had delayed or completely halted tumor growth, while those receiving unmodified T cells showed little effect. Analyses of the immune cells inside the tumors revealed that the engineered T cells were better able to persist, maintain a stem-like state, and resist exhaustion, a common limitation of immune therapies.
"Using advanced structural studies at atomic resolution, we were able to demonstrate how a tiny change, just one amino acid in the interface between a T cell receptor and a prostate cancer protein called PAP, can extend the bond lifetime, dramatically boosting the T cell's ability to kill tumors in living models," said Dr. Xiaojing Tina Chen, co-first author of the study and a postdoctoral scholar in the Department of Molecular and Cellular Physiology at the Stanford School of Medicine. Chen is a recipient of the Walter Benjamin Fellowship awarded by the German Research Foundation (Deutsche Forschungsgemeinschaft).
"This work shows that tumor control can be linked to a single molecular bond," added co–first author Dr. Zhiyuan Mao , a postdoctoral scholar in the Department of Microbiology, Immunology & Molecular Genetics and the Department of Molecular and Medical Pharmacology at the David Geffen School of Medicine at UCLA. Mao is also a recipient of the UCLA JCCC Postdoctoral Fellowship, the Prostate Cancer Foundation (PCF) Young Investigator Award, and a Cancer Research Institute (CRI) Irvington Postdoctoral Fellowship.
Impact of the findings
The study demonstrates that catch bond engineering can make T cells much stronger against prostate cancer while avoiding the risks of traditional T cell receptor engineering, including attacks on healthy tissue.
The findings also suggest a new way to predict which T cell therapies will succeed. By measuring how long T cells form bonds with tumor targets under mechanical force, a method called the biomembrane force probe, researchers can more accurately predict which engineered cells will be most effective in eliminating tumors.
"These findings suggest that catch bond engineering could be a generalizable strategy to enhance T cell therapies for many cancers," said Garcia.
"By creating T cells that are stronger, longer-lasting, and highly precise, the approach moves the field closer to safer and more effective adoptive cell therapies for patients," said Witte, who is the founding director emeritus of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and co-director of the PICI Center at UCLA.
About the research team
The study's other senior authors include Brian D. Evavold of the University of Utah School of Medicine; Tanya Stoyanova and John K. Lee of the David Geffen School of Medicine at UCLA; Zinaida Good of Stanford Medicine; and Naomi R. Latorraca of the Columbia University Irving Medical Center. Additional authors from UCLA include Jami McLaughlin, Donghui Cheng, Caitlin Gee, Miyako Noguchi, and Shiqin Liu.
This research was primarily supported by the Parker Institute for Cancer Immunotherapy, the National Institutes of Health, the Howard Hughes Medical Institute, the German Research Foundation (Deutsche Forschungsgemeinschaft), and the UCLA Health Jonsson Comprehensive Cancer Center.
