NUS Medicine: DUSP4 protein supports CD8+ T cells and boosts CAR-T in mouse colorectal cancer

Researchers at the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine), and collaborators report that the phosphatase DUSP4 helps CD8+ T cells keep their anti-tumour function in colorectal cancer. The team, led by Associate Professor Zhang Yongliang, published the work in Nature Communications; the article is dated 15 August 2026 doi.orgNature Communicationsdoi.orgOpen source ↗. The experiments were done in mouse models and human cells, and the authors combined them with clinical data.

DUSP4 and CD8+ T cell function

DUSP4 belongs to the dual-specificity phosphatases, which remove phosphate groups from serine/threonine and tyrosine residues of proteins. In male mouse models of colorectal cancer induced with AOM/DSS, global DUSP4 deficiency increased tumour development and weakened CD8+ T cell-mediated anti-tumour immunity doi.orgNature Communicationsdoi.orgOpen source ↗. The T cells produced fewer cytotoxic molecules and showed more signs of exhaustion, according to the authors.

The team also analysed tumour tissue from 105 colorectal cancer patients. Lower DUSP4 expression was associated with shorter overall survival, and a similar trend was seen in an independent dataset doi.orgNature Communicationsdoi.orgOpen source ↗. Removing DUSP4 from cancer cells had little effect, while its loss in blood-forming cells weakened CD8+ T cell responses and increased tumour development in mice. The authors conclude that DUSP4 acts mainly on immune cells.

ERK2–KLF2 pathway and CAR-T cells

Mechanistically, DUSP4 knockout increased ERK2-mediated expression of Klf2, a regulator of T cell activation. This in turn suppressed KLF2-mediated cytotoxic programmes doi.orgNature Communicationsdoi.orgOpen source ↗.

To test a practical application, the researchers used CRISPR activation (CRISPRa) to raise DUSP4 activity in human anti-CD19 CAR-T cells. In a xenograft mouse model with CD19-carrying colorectal cancer cells, the modified cells proliferated more readily and showed stronger cytotoxicity than standard CAR-T cells. Tumours in treated animals were smaller and lighter doi.orgNature Communicationsdoi.orgOpen source ↗.

Limits of the result

The authors stress that the CAR-T findings are preclinical. The cancer cells in the model were engineered to carry CD19, the CAR-T target, and further studies are needed to evaluate the approach clinically. Next, the group plans to study how DUSP4 itself is regulated in tumours, identify other molecules through which it controls T cell function, and look for ways to enhance DUSP4 activity in engineered T cells.