Aging rewires genetic dependencies in antitumor T cells.

Abstract

The aged tumor microenvironment can impair antitumor T cell function, but the molecular regulators that become limiting in this setting remain poorly defined. In a recent issue of Cell, Chen and colleagues harness in vivo CRISPR screening to compare the effects of genetic perturbations in tumor-reactive CD8+ T cells across young and aged hosts. The screen reveals that increased T cell persistence or an effector-like transcriptional state does not necessarily translate into improved tumor control and identifies Dusp5 and Zfp219 as distinct functional regulators. DUSP5 broadly restrains ERK-dependent proliferation, and its loss improves tumor control in both young and aged mice. ZFP219, by contrast, preferentially limits cytotoxicity in aged hosts; its deletion increases granzyme expression and improves tumor control specifically in the aged setting. Human tumor datasets show that ZNF219 expression in intratumoral CD8+ T cells increases with age and is associated with poorer clinical outcomes. Moreover, Zfp219 loss enhances the response to PD-1 blockade in aged mice, producing complete tumor clearance in a subset of animals and durable protection after rechallenge. Together, these findings show that host age can reshape the functional consequences of T cell perturbations and reveal age-dependent genetic vulnerabilities with potential therapeutic relevance.