Research Spotlight: Restoring aging T cell function to make them effective at fighting cancer

Alex C.Y. Chen, PhD, and Debattama (Deb) Sen, PhD, of the Mass General Brigham Cancer Institute, are the lead and senior authors, respectively, of a paper published in Cell, “CRISPR screens identify targets to rescue age-related T cell dysfunction in cancer.”

Q: What challenges or unmet needs make this study important?

As a person gets older, their immune system becomes worse at fighting disease. This age-related immune decline, also known as immune aging, is a critical barrier to successful cancer immunotherapy. However, we still do not fully understand what causes immune aging, making it difficult to identify drug targets that could help overcome this barrier.

Q: What central question(s) were you investigating?

In our prior work, we found that the aged tumor microenvironment (TME) pushes CD8+ killer T cells toward dysfunction, reducing their ability to fight cancer. Therefore, our goal is to identify new ways to reinvigorate CD8+ killer T cells in the TME and make them more effective by improving their persistence and tumor-killing capacity.

Q: What methods or approach did you use?

To achieve this goal, we performed a “CRISPR pooled screen,” making changes in multiple genes simultaneously to figure out the best possible target rather than studying genes one at a time. This approach allows us to identify the regulators of T cell dysfunction within the aged TME in a scalable and efficient way. We developed this screening method using aged tumor-bearing mice, whose tumor microenvironment closely mimics what tumor cells and T cells encounter in older cancer patients.

Q: What did you find?

Our results suggest that dual specificity phosphatase 5 (Dusp5) and zinc finger protein 219 (Zfp219) are two key regulators of T cell dysfunction, which leads to poor tumor control in aged hosts.

Dusp5 acts as a “brake” on ERK signaling pathways that help T cells increase in number. When  Dusp5  is removed, ERK signaling becomes more active, allowing T cells to proliferate more effectively.

Zfp219 acts as an "off switch" for genes involved in producing granzymes, tumor-fighting enzymes. When  Zfp219  is knocked out, T cells increase secretion of granzymes (e.g., GZMA, GZMB), making them better at killing tumor cells.

Q: What are the real-world implications, particularly for patients?

We found that older adults have higher levels of ZNF219, the human counterpart of the mouse gene Zfp219, in T cells within their tumors. Higher ZNF219 levels were also associated with poorer responses to immune checkpoint blockade and shorter survival, likely because these T cells do not efficiently kill tumor cells. Therefore, ZNF219 could serve as a new age-related prognostic marker for cancer patients.

Moreover, blocking ZNF219 activity could be a promising approach to improving T cell function as a cancer treatment for older adults. Although ZNF219 itself is difficult to target with drugs, newer approaches that genetically modify a patient's own T cells, such as CAR-T cell therapy or other engineered T cell treatments, may provide a practical way to reduce ZNF219 activity and strengthen the body's ability to fight cancer.

Authorship: In addition to Chen and Sen, Mass General Brigham authors include Keely Ji, Cansu Yerinde, Nelson Knudsen, Kevin Bi, Shumeng Hao, Daniela Martinez, Thomas Carmona-LaSalle, Kazuhiro Taguchi, Katherine Xu, Elizabeth Seider, Maria Zschummel, Linda Nieman, Kathleen Yates, Francesca Gazzaniga, Thorsten Mempel, Robert Manguso and Nir Hacohen. Additional authors include Vasyl Zhabotynsky, Marc Schwartz and Brian Miller.

Paper cited: Chen, ACY.,  et al.  “CRISPR screens identify targets to rescue age-related T cell dysfunction in cancer.”  Cell.  DOI: https://doi.org/10.1016/j.cell.2026.07.016

Funding: Sen was supported by funding from the Melanoma Research Alliance, the V Foundation for Cancer Research and the NIH (DP2AI176139). Chen was supported by funding from the NIH (T32CA921643) and (K99CA296769). Ji was supported by the National Science Foundation Graduate Research Fellowship under grant (DGE 2140743). Gazzaniga was supported by funding from the Cancer Research Institute and the Victoria’s Secret Global Fund for Women’s Cancers Career Development Award in Partnership with Pelotonia and AACR. Miller is supported by the Burroughs Wellcome Fund Career Award for Medical Scientists. Carmona-LaSalle was supported by the following NIH awards (T32GM007753, T32GM144273, F30CA305947).

Disclosures: Miller has consulted for Cellarity, LifeOmic and Telix Pharmaceuticals. Hacohen holds equity in and advises Repertoire Immune Medicines, CytoReason and Danger Bio/Related Sciences; owns equity and has licensed patents to BioNtech; and receives research funding from Bristol Myers Squibb, Moderna, Takeda and Calico Life Sciences. Other authors declare no competing interests. Hacohen has a family member who is a member of the Cell Press journal advisory board.

About Mass General Brigham

Mass General Brigham is an integrated academic health care system, uniting great minds to solve the hardest problems in medicine for our communities and the world. Mass General Brigham connects a full continuum of care across a system of academic medical centers, community and specialty hospitals, a health insurance plan, physician networks, community health centers, home care, and long-term care services. Mass General Brigham is a nonprofit organization committed to patient care, research, teaching, and service to the community. In addition, Mass General Brigham is one of the nation’s leading biomedical research organizations with several Harvard Medical School teaching hospitals. For more information, please visit massgeneralbrigham.org.