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.