In mice, two genes weaken aging T cells against cancer

In aged tumor-bearing mice, killer immune cells were losing the fight inside the tumor. At the Mass General Brigham Cancer Institute, researchers led by Alex C.Y. Chen and Debattama Sen have now used a gene screen to identify two regulators that may help explain why aging weakens cancer immunotherapy. Their study was published in Cell in 2026.

The team built a pooled CRISPR screen, a method that changes many genes simultaneously instead of testing them one by one. They ran it in aged mice carrying tumors, an experimental setting designed to reflect the tumor environment encountered by older cancer patients. The focus was on CD8 killer T cells, which need both persistence and tumor-killing capacity to control cancer.

The first target, Dusp5, acts as a brake on ERK signaling, a pathway that helps T cells multiply. When researchers removed Dusp5, ERK signaling became more active and the T cells proliferated more effectively. The second, Zfp219, functions as an off switch for genes involved in producing granzymes—enzymes that T cells release to kill tumor cells. Removing it increased secretion of GZMA and GZMB.

The human counterpart, ZNF219, also appeared in tumor-infiltrating T cells from older adults. Higher levels were associated with poorer responses to immune checkpoint blockade and shorter survival. That makes ZNF219 a potential age-related prognostic marker, but the association does not yet show that blocking the gene will improve outcomes.

So what changes concretely? The findings give researchers two molecular handles for trying to restore T cell performance in older patients, potentially through CAR-T therapy—treatment using a patient's own genetically modified T cells—or other engineered T cell approaches. ZNF219 may be difficult to target with conventional drugs, and no human treatment has been tested here; the evidence remains at the preclinical stage.