Chimaeric antigen receptor T-cell therapy — CAR T for short — has been a major advance in treating blood cancers like leukaemia and lymphoma.

But the immunotherapy has struggled against solid tumours for two main reasons: tumour cells often don’t share one consistent surface target, and many solid tumours are protected by a dense network of scar tissue and immune-suppressive cells that blocks T cells.

Now, researchers at Memorial Sloan Kettering Cancer Centre (MSK) and collaborators have developed a new type of CAR T cell designed to address both problems at once — by attacking cancer cells as well as supportive cells in the tumour microenvironment that bear a surface protein called uPAR.

The preclinical findings, published in Cell, still need to be tested for safety and efficacy in people.

“This new approach shrank several types of solid tumour in the lab, including lung, pancreatic, and ovarian cancers — and even cleared metastases in some experiments,” says co-senior study author Scott Lowe, PhD, Chair of the Cancer Biology and Genetics Programme, the Geoffrey Beene Chair for Cancer Biology at MSK’s Sloan Kettering Institute, and a Howard Hughes Medical Institute Investigator.

“In our laboratory models, these engineered cells selectively eliminated not only solid tumour cells, but also the uPAR-positive fibroblasts and immunosuppressive myeloid cells that provide a protective environment for the tumour to grow in,” he adds.

The study was led by first author Zeda Zhang, PhD, a postdoctoral researcher in the Lowe Lab.

Senior authors on the study include Dr. Lowe; Michel Sadelain, MD, PhD, who recently moved his lab from MSK to Columbia University; and Aveline Filliol, PhD, a senior scientist in the Lowe Lab.

The team tested the effectiveness of the uPAR-targeted CAR T cells in a range of preclinical systems, including cancer cells, human tumours grown in mice, and mouse models that mimic metastatic disease.

Overall, the new approach shows significant power to fight cancer with limited impact on other healthy tissues and cells, the researchers report.

In a mouse model of ovarian cancer, for example, uPAR-targeting CAR T cells were able to wipe out metastases, leading to durable remissions.

And mice whose tumours had been eliminated also resisted developing new tumours when researchers tried to introduce cancer again later, indicating the CAR T cells remained active.

Additionally, a single, adjuvant dose of the engineered cells after surgery eliminated residual disease in mice, while surgery alone helped only temporarily.

The urokinase plasminogen activator receptor — or uPAR — is a protein found on the outside of cells.

In healthy tissue, very few cells have uPAR on their surface; it’s primarily found on myeloid immune cells, and helps with processes associated with wound healing.

But in cancer, which co-opts the body’s normal wound healing programmes, both tumour cells and cells in the fibrous “niche” that support the tumour produce a lot more uPAR.

By focusing on uPAR, the new approach allows researchers to target cells in a particular state rather than a specific type of cell.

The findings dovetail with recent work from the Tuomas Tammela Lab, which is also within the Sloan Kettering Institute’s Cancer Biology and Genetics Programme, showing that even when such cells represent only a subpopulation of the tumour, their elimination can lead to tumour collapse — and highlighting the functional importance of these specialised cell states.

The CAR T cells that target CD19 in leukaemia and lymphoma, for example, primarily target B cells — including cancer cells that develop from B cells.

uPAR, on the other hand, tends to show up on the most dangerous, identity-shifting cancer cells — as well as on nearby support cells that are stuck in a constant wound-healing mode, building scar tissue and suppressing the immune response.

“Our work shows uPAR marks not only malignancy, but also the broader ecosystem that supports cancer — a feature that sets uPAR apart from other cell-surface targets,” Dr. Zhang says.

The researchers became interested in uPAR through studies of “cellular senescence” — a brake the body imposes on damaged or stressed cells, which stops them from dividing.

Some standard cancer treatments like chemotherapy can also push cells into senescence — raising uPAR levels in tumour cells.

In the study, researchers found uPAR was elevated in 12 of the 14 human cancer types they analysed, with especially high levels in some types of ovarian, pancreatic, colon, lung, and brain cancers.

“High uPAR expression was most strongly associated with mutations that compromise p53 — the tumour-suppressor often called the ‘guardian of the genome’ — and activating mutations in KRAS and other genes in the RAS pathway,” Dr. Filliol says.

“We also found high uPAR was associated with the activation of genes that are important for cellular plasticity, inflammation, and fibrosis, which are all hallmarks of aggressive cancer.”

In preclinical experiments, uPAR-targeted CAR T cells were effective at killing cancer cells across multiple cancer models.

And their effect could be further enhanced by combining them with senescence-inducing treatments such as the chemotherapy agent cisplatin, which raised uPAR levels and made tumour cells easier for the engineered T cells to attack.

Testing showed that the engineered cells worked most effectively when there were at least 1,500 uPAR molecules on the surface of each cell.

And to make the engineered cells even more effective, the team developed the new CAR T cells using new uPAR-binding molecules designed to recognise a form of uPAR that is less likely to be shed from the cell surface due to inflammation.

Importantly, uPAR-directed CAR T cells could attack tumours from multiple angles, Dr. Sadelain says.

“We’re not just targeting uPAR on the surface of tumour cells, but also the uPAR-expressing fibroblasts and myeloid cells in a tumour’s supporting ‘niche,” he says.

“That is something unique.”

The research is illustrative of efforts supported by the Marie-Josée and Henry R. Kravis Cancer Ecosystems Project, for which Dr. Lowe serves as scientific director.

This initiative is focused on understanding cancer not simply as a genetic disease, but as an interconnected ecosystem of cells, tissues, and signalling networks.

By framing cancer in this way, the programme aims to enable the development of next-generation therapies — such as uPAR CAR T cells — that target not only tumour cells, but also the surrounding niche that supports their growth and progression.

“It’s increasingly clear that the progression of a malignant tumour isn’t just about transformations happening within cells, but about coordinated interactions between cells and nearby tissues to develop tumour-supportive ecosystems,” Dr. Lowe says.

The researchers believe targeting uPAR also holds promise for diseases beyond cancer.

“The same types of cells and tissues that we find around tumours are important in other fibrotic, degenerative, and inflammatory disorders,” Dr. Lowe says.

Beyond CAR T cells, uPAR might also be targeted with antibody drug conjugates, antibody-delivered radiation, and CAR-based natural killer cell treatments, the study authors note.

The researchers also showed two potential ways to monitor uPAR-high disease without a biopsy: measuring suPAR (a soluble fragment of uPAR) in blood, and using uPAR-targeted PET scans to spot tumours and metastases and track the cancer’s response to treatment over time.

Source: Memorial Sloan Kettering Cancer Center