Protein DUSP4 Boosts CAR-T Cells Against Colorectal Cancer in Mice

Raising the level of a single protein, DUSP4, made engineered immune cells multiply faster and shrink colorectal tumours in laboratory models, according to researchers at the National University of Singapore. The DUSP4 CAR-T findings, announced by NUS Medicine on 4 November, come from a study published in Nature Communications.

The work tackles one of the stubborn problems in cancer immunotherapy. Immune cells that can recognise and kill cancer tend to tire once they are inside a solid tumour, gradually losing their ability to multiply and attack. The Singapore team says DUSP4 helps hold off that decline, and that boosting it could one day make cell therapies work better against cancers such as colorectal cancer. For now, the evidence comes from patient tissue and lab experiments, not from treating anyone.

DUSP4 keeps CD8+ T cells from wearing out

The research was led by Associate Professor Zhang Yongliang of the Department of Microbiology and Immunology and the Immunology Translational Research Programme at NUS Medicine. It focuses on CD8+ T cells, the immune cells that can directly kill cancer cells.

According to the release, when DUSP4 was missing these cells became less effective and showed more signs of exhaustion, and lab models developed a greater colorectal tumour burden. The cells made fewer cancer-killing molecules. The team also found that DUSP4 mainly works through the immune system rather than by slowing cancer cells directly: removing it from the cancer cells had little effect, while losing it in blood-forming cells weakened T-cell responses and increased tumour growth.

The researchers traced how this happens. Without enough DUSP4, a signalling protein called ERK2 becomes more active and raises levels of another, KLF2, which suppresses the genetic programmes T cells use to kill cancer cells. DUSP4 keeps that pathway in check.

“CD8+ T cells are among the immune system’s main weapons against cancer, but prolonged exposure to tumours can gradually weaken their ability to function,” Assoc Prof Zhang said. “Our findings suggest that DUSP4 helps keep these cells in a state where they can continue to multiply and attack cancer cells effectively.”

Patient samples tie low DUSP4 to poorer survival

The team analysed tumour tissue from 105 colorectal cancer patients. Lower DUSP4 levels were associated with poorer overall survival, and the release says a similar trend was seen in an independent dataset.

That is an association, not proof that DUSP4 itself changes how long patients live. But it gives the lab findings a link to real patients, which is part of why the researchers went on to test whether the protein could be put to work in a treatment.

DUSP4 CAR-T cells shrank tumours in lab models

CAR-T therapy takes a patient’s own T cells and genetically engineers them to recognise cancer. It has transformed the treatment of some blood cancers, but solid tumours have proved much harder, partly because the engineered cells become exhausted in the tumour environment.

The NUS team raised DUSP4 activity in human CAR-T cells using a gene-activation technique. Compared with standard CAR-T cells, the DUSP4-enhanced cells multiplied more readily and killed colorectal cancer cells more effectively in laboratory experiments. In lab models, treatment with them produced smaller and lighter tumours than standard CAR-T cells.

“By increasing DUSP4 activity, we were able to improve both the growth and cancer-killing capacity of CAR-T cells in our experimental models,” said Professor Nicholas Gascoigne of NUS Medicine, who is also a professor at Augusta University in the US. “This gives us a potential strategy for engineering T cells that are better able to maintain their function in the difficult environment of solid tumours.”

A durability fix, but with a borrowed target

The researchers are careful about what this shows, and the most important caveat is easy to miss. The colorectal cancer cells in the CAR-T model were engineered to carry CD19, the target the CAR-T cells recognise. CD19 is a blood-cancer marker; real colorectal tumours lack it. So the experiment tested whether DUSP4 makes CAR-T cells last longer and hit harder inside a colorectal tumour setting, not whether a CAR-T therapy can find and kill natural colorectal cancer.

That distinction matters because solid-tumour CAR-T has two separate problems: finding a target that sits on cancer cells but not healthy tissue, and keeping the cells working once they arrive. DUSP4 speaks to the second. If it holds up, it is the kind of add-on that could in principle be combined with whatever target future therapies use, which is why a result on durability can be useful even before the targeting problem is solved.

It also fits a wider shift in cancer immunology away from simply waking the immune system up and towards keeping it switched on. TSN has covered that theme from several angles, from an early NIH-led trial of a T-cell drug in resistant tumours to a KRAS pancreatic cancer vaccine that primed T cells despite missing its main goal. That vaccine is a reminder that strong immune signals are no guarantee of patient benefit.

The patient data deserve the same caution. A link between low DUSP4 and poorer survival in 105 samples is a reason to keep looking, not a biomarker ready for clinics. Much as with the AI heart MRI study from UCL, a survival association in existing data is a starting point that needs testing forward in time. The distance from a mouse tumour to an approved therapy is long, as the years behind the personalised mRNA melanoma therapy from Merck and Moderna show.

What the Singapore team plans next

The team says it will next study how DUSP4 itself is regulated within tumours, look for other molecules through which it controls T-cell function, and explore ways of boosting DUSP4 in engineered T cells. The work was funded by Singapore’s National Research Foundation, the National Medical Research Council and the Ministry of Education.

The open question is the one the researchers name themselves: whether the effect survives a real colorectal tumour target and, eventually, a clinical study in patients.

Sources

• NUS Medicine press release, “NUS Medicine study identifies protein that could strengthen cancer-fighting T cells against colorectal cancer”, 4 November 2026
• Nature Communications, “DUSP4 promotes anti-tumor CD8+ T cell function and boosts CAR-T cell efficacy in mouse colorectal cancer”

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