Over the past few decades, the idea of modifying a patient’s own immune cells to recognize and destroy cancer has evolved from concept to reality. So-called “adoptive T cell therapy” has emerged as one of the most promising frontiers in cancer therapy. It comes in a few different flavors, such as isolating and expanding T cells that are already capable of attacking the tumor or genetically engineering T cells with new receptors that enable them to target molecules expressed in the tumor. While these therapies have achieved clear success in certain blood cancers, progress against solid tumors has proven far more challenging.
In many solid tumors, immune cells struggle to survive because the tumor environment is both toxic—filled with signals that suppress T cell function and growth like the cytokine TGF-β—and deprived of essential nutrients and growth factors like IL-2. However, systemically blocking TGF-β with drugs or supplying exogenous IL-2 to the patient can cause severe toxicity-related side effects and paradoxically expand suppressive immune cells.
Research led by Dr. Yapeng Su and Dr. Ashley Thelen in the Greenberg Lab of the Translational Science and Therapeutics Division at Fred Hutchinson Cancer Center sought to help T cells more effectively fight cancer by rewiring how the T cells interpret their environment.
“We designed an immuno-fusion protein (IFP) that acts like a smart adapter—it converts the harmful TGF-β signal into an IL-2 signal that sustains T cell survival, essentially turning a vulnerability into a strength.” Dr. Su shared. This work was recently published in PNAS.
The researchers did this by merging the extracellular domains of the TGF-β receptor (TGF-βR) with the intracellular signaling tails of the IL-2 receptor (IL-2Rβ and IL-2Rγ). These synthetic receptors allow incoming TGF-β signals, normally suppressive, to instead activate STAT5, the downstream effector of IL-2 signaling that promotes T cell survival and proliferation. It’s like rewiring a brake pedal to act as an accelerator. Normally, TGF-β is a ‘stop’ signal that suppresses T cells, but the engineered receptor turns that same input into a ‘go’ signal that fuels their activity.
The researchers mixed and matched different combinations of receptor, transmembrane and intracellular domain isoforms from the TGF-β and IL-2R families to identify which arrangement most effectively converted TGF-β binding into IL-2-like activation, producing strong STAT5 phosphorylation while dampening canonical TGF-β/SMAD2-3 signaling. When expressed in primary human CD8⁺ T cells, these IFPs enabled the cells to thrive in TGF-β-rich conditions, proliferating robustly where normal T cells would arrest. RNA-sequencing confirmed that these rewired cells turned on IL-2-responsive and effector-function genes while suppressing inhibitory pathways.
To put their concept to the test, the team expressed their TGF-β/IL-2 IFPs alongside a mesothelin-specific T cell receptor (TCR) in T cells. Mesothelin is a marker expressed in pancreatic cancer; these mesothelin-specific TCR-T cells were developed by the Greenberg Lab and have advanced to clinical trials. In co-cultures with a pancreatic tumor cell line and exogenous TGF-β, TGF-β/IL-2 IFP-expressing TCR-T cells eliminated tumor cells more efficiently and maintained greater proliferation and viability than mesothelin TCR-T cells without IFPs. Over two weeks of continuous tumor exposure, the IFP-modified cells retained high expression of cytotoxic (tumor fighting) molecules such as granzyme B, IFN-γ, and TNF-α, and exhibited a gene expression profile consistent with sustained anti-tumor immunity.
The approach also avoids the toxicities of systemic IL-2 or broad TGF-β blockade, as signaling occurs only within engineered T cells encountering TGF-β in the tumor microenvironment. The authors propose that such “signal-reprogramming” receptors could be integrated into next-generation armored T cell therapies, either alone or in combination with checkpoint blockade, to improve efficacy in otherwise refractory solid tumors.
“This innovation has great potential to make T cell therapy far more effective for a wide range of solid tumors that have resisted previous immune treatments.” says Su. The IFP can be added to TCR-T cells (or CAR-T cells) to help them function better; the engineered TCR is like the steering wheel and the IFP is the engine upgrade.
He adds: “This is just the beginning of learning how to “armor up” our engineered T cells to thrive in the tumor’s harsh environment. With this work, we’ve addressed two major challenges—TGF-β suppression and IL-2 deprivation—but many others remain that can limit therapeutic activity. Our next step is to identify and overcome additional barriers that tumor cells create to evade immune attack. Each breakthrough brings us closer to designing T cells that can fully unleash their potential against even the most resistant cancers.”
The spotlighted research was funded by the NIH, the Fred Hutch Translational Data Science Integrated Research Center, the Parker Institute for Cancer Immunotherapy, the Damon Runyon Cancer Research Foundation Quantitative Biology Fellowship, the Mahan Fellowship at Herbold Computational Biology Program of Fred Hutch, the Hartwell Innovation Fund, and Swim Across America.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Member Dr. Philip Greenberg contributed to this research.
*Su Y, *Thelen A, Wirth LV, Jenkins CM, Mak SR, Chen DG, Gottardo R, Greenberg PD. 2025. A TGF-βR/IL-2R immunomodulatory fusion protein transforms immunosuppression into T cell activation to enhance adoptive T cell therapy. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.2516951122. *These authors contibuted equally.
Science Spotlight writer Kelly Mitchell is a postdoctoral fellow in the Paddison Lab at Fred Hutch Cancer Center. She utilizes live cell reporters and CRISPR screening to study how glioblastoma cancer cells resist chemotherapy and radiation treatment. She obtained her PhD in cellular biology from Albert Einstein College of Medicine.