Researchers demonstrated that the dual-specificity phosphatase DUSP4 supports the cytotoxic activity of CD8+ T cells against colorectal cancer and enhances CAR-T cell efficacy in mouse models, according to a study published in Nature Communications.
Clinical data analyzed in the study revealed that colorectal cancer patients with lower DUSP4 expression across tumor tissue experience shorter overall survival compared to patients with higher expression levels. In laboratory tests using chemically induced male mouse colorectal cancer models, global DUSP4 deficiency accelerated tumor development and weakened CD8+ T cell-driven immune responses.
Molecular analysis identified the underlying signaling pathway. Knocking out DUSP4 increases ERK2-mediated expression of the T cell activation regulator Klf2, which subsequently suppresses KLF2-mediated cytotoxic programs inside the immune cells.
The study also tested genetic intervention in a CD19-positive colorectal cancer xenograft mouse model. Activating DUSP4 through CRISPR activation promoted both the proliferation of anti-CD19 CAR-T cells and their anti-tumor cytotoxicity against the tumors.
The peer-reviewed paper was published on August 15, 2026, after submission in December 2025. Co-lead authors Heng Li, Clara K. T. Koh, and Tianshuai Zhang conducted the work across institutions including the National University of Singapore, Shanghai Changhai Hospital, Guangzhou University of Chinese Medicine, and Augusta University, with support from the Singapore National Medical Research Council, Singapore Ministry of Education, and Singapore National Research Foundation.
