Cell：体内CRISPR筛选，发现让衰老T细胞返老还童的新靶点，恢复老年癌症患者的抗癌能力

TL;DR - A Cell paper from Debattama R. Sen's lab (Harvard Medical School/MGH, published July 29, 2026) used in vivo single-cell CRISPR screens in young vs. aged tumor-bearing mice to identify Dusp5 and Zfp219 as key drivers of age-related CD8+ T cell dysfunction. It matters because it names actionable targets for restoring anti-tumor immunity in elderly cancer patients, a rapidly growing population.

• Screens were run on naive CD8+ T cells transferred into young or aged tumor-bearing mice, rather than the more common in vitro or pre-activated in vivo designs, to capture physiological priming, differentiation, and effector function in the tumor microenvironment.
• Dusp5 knockout raised ERK phosphorylation and broadly boosted T cell proliferation, improving tumor control in both young and aged mice; Zfp219 knockout drove epigenetic reprogramming and restored granzyme/cytotoxic molecule expression, enhancing anti-tumor immunity specifically in aged mice.
• The human ortholog ZNF219 is expressed at higher levels in intratumoral CD8+ T cells of older cancer patients and correlates with worse survival after immunotherapy.
• Zfp219 knockout synergized with anti-PD-1 blockade, expanding effector-like CD8+ T cells and achieving tumor clearance in aged mice.