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CRISPR screens identify targets to rescue age-related T cell dysfunction in cancer

Alex C Y Chen1, Keely Y Ji1, Cansu Yerinde1

  • 1Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA.

Cell
|July 29, 2026
PubMed

Insights

Immune aging harms T cell function, impacting cancer treatment. Researchers identified Dusp5 and Zfp219 as key factors in T cell dysfunction, offering new targets to improve cancer immunotherapy in older adults.

Area of Science:

  • Immunology
  • Oncology
  • Aging Research

Background:

  • Immune aging significantly impairs T cell responses, negatively affecting tumor control and cancer immunotherapy efficacy.
  • The specific molecular drivers of T cell dysfunction in the context of aging tumors are not well understood.

Purpose of the Study:

  • To identify key regulators of CD8+ T cell persistence and effector function within aged tumors.
  • To explore the potential of targeting identified regulators to rejuvenate anti-tumor immunity in aging cancer patients.

Main Methods:

  • Utilized single-cell CRISPR screens to identify critical genes regulating T cell function in aged tumors.
  • Investigated the effects of Dusp5 and Zfp219 loss on T cell signaling, epigenetics, and anti-tumor activity in murine models.
  • Analyzed human patient data to correlate ZNF219 levels with clinical outcomes in cancer immunotherapy.

Main Results:

  • Dusp5 loss enhanced T cell proliferation by increasing extracellular signal-regulated kinase (ERK) phosphorylation.
  • Zfp219 deletion promoted epigenetic reprogramming, increased cytotoxic molecule expression, and boosted anti-aging immunity.
  • Higher ZNF219 levels in older cancer patients' T cells correlated with poorer immunotherapy survival.
  • Zfp219 ablation synergized with immune checkpoint inhibitors to enhance anti-tumor CD8+ T cell responses and achieve tumor clearance in aged mice.

Conclusions:

  • Dusp5 and Zfp219 are critical regulators of age-related T cell dysfunction in tumors.
  • Targeting Dusp5 and Zfp219 presents a promising strategy to restore anti-tumor immunity in elderly cancer patients.
Keywords:
T cellsantitumor immunitycancer immunology and immunotherapyimmune agingin vivo single-cell CRISPR screen

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