Mass General Brigham researchers have identified two genetic regulators that appear to drive the decline of cancer-fighting T cells in older bodies, offering a possible explanation for why cancer immunotherapies often work less effectively with age. In a study published in Cell, the team used large-scale CRISPR screening in aged, tumor-bearing mice to uncover molecular “brakes” that weaken CD8+ T cells inside the tumor microenvironment. The findings point to two genes, Dusp5 and Zfp219, as potential targets for restoring the ability of immune cells to multiply, persist and destroy tumor cells. One of the genes, ZNF219, the human counterpart of mouse Zfp219, was also associated with poor treatment responses and shorter survival in older cancer patients.
The study addresses a growing problem in oncology. As people age, the immune system gradually loses some of its ability to recognize and eliminate abnormal cells, a process often described as immune aging or immunosenescence. This decline affects many components of immunity, including the activity of T cells that are essential for controlling cancer. Modern immunotherapies, such as immune checkpoint inhibitors, work by releasing inhibitory signals that restrain T cells. Yet removing those external brakes may not be enough when T cells have already been reshaped by an aged tumor microenvironment and have lost the internal capacity to expand or kill cancer cells efficiently. Understanding the biological causes of this dysfunction could help researchers design treatments specifically for older adults, who carry much of the global cancer burden.
The new work builds on earlier research by the Mass General Brigham team showing that aging changes the tumor microenvironment, the complex network of cancer cells, immune cells, blood vessels and signaling molecules surrounding a tumor. In older hosts, this environment can push CD8+ killer T cells toward a dysfunctional state. These cells may still reach the tumor and recognize malignant targets, but they become less capable of proliferating, surviving for long periods or releasing the toxic molecules needed to kill cancer cells. The researchers therefore focused on a central question: which genes inside T cells are responsible for this age-associated loss of function, and can disabling those genes restore antitumor activity?
To answer that question, the investigators performed a pooled CRISPR screen, a genetic technology that allows scientists to disrupt thousands of genes across a population of cells and then identify which alterations improve or weaken a desired biological response. Instead of examining one candidate gene at a time, the method creates a broad functional map of gene activity. The researchers conducted the screen in tumor-bearing aged mice, an experimental setting designed to capture the conditions encountered by T cells in older patients. The surviving and most effective T cells were then analyzed to determine which genetic changes helped them perform better within the aged tumor microenvironment.
The screen highlighted Dusp5 and Zfp219 as important regulators of separate aspects of T cell dysfunction. Dusp5, or dual specificity phosphatase 5, influences the ERK signaling pathway, a molecular cascade that helps T cells respond to stimulation and produce more copies of themselves. Signaling pathways function through a series of phosphorylation events, in which phosphate groups are added to proteins to alter their activity. Phosphatases remove those phosphate groups and can dampen the signal. In this case, the researchers found that Dusp5 acts as a brake on ERK signaling. Removing the gene allowed ERK activity to rise, helping T cells proliferate more effectively in the aged tumor environment.
The second gene, Zfp219, appeared to control the destructive machinery that T cells use against cancer. The gene encodes a zinc finger protein, a type of DNA-binding regulator that can influence whether particular genes are turned on or off. The researchers found that Zfp219 suppresses genes involved in the production of granzymes, enzymes stored and released by cytotoxic T cells. Granzymes, including granzyme A and granzyme B, enter targeted cells and activate molecular pathways that lead to cell death. When Zfp219 was knocked out, T cells increased their secretion of these tumor-killing proteins and became more effective at damaging malignant cells.
Together, the results suggest that immune aging does not weaken cancer immunity through a single universal mechanism. Instead, it can interfere with several distinct biological programs at once. One pathway limits the ability of T cells to expand, while another restricts the production of molecules required for direct tumor killing. This division of labor may be important for future therapies, because simply increasing the number of T cells in a tumor will not necessarily improve treatment if those cells remain unable to destroy cancer cells. Conversely, boosting cytotoxic activity may have limited impact if the cells cannot persist or reproduce. The two genes identified in the study therefore represent complementary targets for improving both the quantity and quality of the antitumor response.
The researchers also examined whether their findings were relevant to human cancer. They found that older adults had higher levels of ZNF219 in T cells located within their tumors. Increased expression of the gene was associated with poorer responses to immune checkpoint blockade and shorter survival. These observations do not prove that ZNF219 directly causes treatment resistance or poor outcomes, but they suggest that the gene could become an age-related prognostic marker. Measuring ZNF219 activity in tumor-infiltrating T cells might eventually help clinicians estimate how effectively a patient’s immune system is likely to respond to checkpoint therapy. Such a test would require validation in larger, diverse patient groups and across multiple cancer types before it could be used routinely.
Directly targeting ZNF219 with a conventional drug may be difficult because the protein functions as a gene-regulating factor rather than an easily accessible enzyme. The researchers point to engineered T cell therapies as one possible route around that challenge. In approaches such as CAR-T cell therapy, a patient’s T cells are collected, genetically modified in the laboratory and returned to the body after expansion. In principle, these cells could be engineered to reduce or eliminate ZNF219 activity before infusion. Similar strategies might be incorporated into other forms of adoptive cell therapy, potentially creating T cells with stronger granzyme production and greater resistance to the suppressive conditions found in older tumors.
The work remains a preclinical advance rather than an immediately available treatment. The safety of altering Dusp5 or ZNF219 must be carefully assessed, since excessive T cell activation can cause tissue damage, autoimmune reactions or dangerous inflammatory responses. Researchers will also need to determine whether the benefits observed in aged mice can be reproduced in human tumors, which differ widely in their genetics, immune composition and response to therapy. Even so, the study offers a detailed molecular explanation for one facet of immune aging and identifies targets that may be especially relevant to older cancer patients. By showing that age-related T cell dysfunction can be dissected genetically—and potentially reversed—the findings could help move cancer immunotherapy toward treatments designed not only for the tumor type, but also for the biological age of the immune system.
Subject of Research: Age-related T cell dysfunction in cancer and genetic targets for restoring antitumor immunity
Article Title: CRISPR screens identify targets to rescue age-related T cell dysfunction in cancer
Web References: https://www.massgeneralbrigham.org/en/patient-care/services-and-specialties/cancer ; https://www.nature.com/articles/s41590-024-01828-7 ; https://www.cell.com/cell/abstract/S0092-8674(26)00814-7
References: Chen, ACY, et al. “CRISPR screens identify targets to rescue age-related T cell dysfunction in cancer.” Cell. DOI: 10.1016/j.cell.2026.07.016
Keywords: cancer immunotherapy, immune aging, T cells, CD8+ T cells, CRISPR screening, Dusp5, Zfp219, ZNF219, tumor microenvironment, immune checkpoint blockade, granzymes, CAR-T therapy, cancer prognosis
