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

Loss of Zfp219 enhances antitumor immunity in aged mice by inducing epigenetic reprogramming and increasing cytotoxic molecule expression, leading to tumor clearance.

• Why it matters: Age-related T cell dysfunction impairs tumor control and reduces effectiveness of cancer immunotherapy, creating a need to identify targets to restore T cell function in older patients.
• What they did: Single-cell CRISPR screens identified Dusp5 and Zfp219 as key regulators of CD8+ T cell persistence and differentiation in aged tumors; Zfp219 deletion increased cytotoxic molecules and improved antitumor responses.
• The result: Zfp219 ablation combined with immune checkpoint inhibitors expanded effector-like CD8+ T cells and resulted in tumor clearance in aged mice, suggesting potential therapeutic targets for older cancer patients.