High ZFP36 Family Expression in Exhausted T Cells Is Associated With Impaired Antitumor Effector Function

ABSTRACT Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by reinvigorating antitumor immunity; however, a substantial proportion of patients show primary resistance or later relapse. To investigate T cell states associated with reduced ICI efficacy, we performed single‐cell RNA sequencing (scRNA‐seq) on tumor‐infiltrating lymphocytes (TILs) from a patient experiencing rapid recurrence under PD‐1 blockade. Our analysis identified elevated expression of the ZFP36 family of RNA‐binding proteins within exhausted CD8 + T cells (T ex cells) in this progressing tumor. The ZFP36 family is known to destabilize target mRNAs by binding to AU‐rich elements in their 3′ untranslated regions (3′ UTRs). In EL4 T cells, Zfp36 overexpression accelerated the decay of the effector cytokine mRNAs Tnf , Il2 , and Ifng , thereby impairing cytokine production. This process is exacerbated by hypoxia. Furthermore, high ZFP36 family expression correlates with poor prognosis in ICI‐treated patients in a public bulk tumor transcriptomic dataset. These findings suggest that tumor microenvironment (TME)‐induced hypoxia upregulates the ZFP36 family in T ex cells, which in turn suppresses cytokine production via post‐transcriptional regulation, potentially contributing to impaired antitumor effector function.