Adoptive T cell therapy (ACT) has achieved remarkable clinical responses in hematologic malignancies but remains limited by progressive T cell dysfunction under chronic antigen stimulation. Here, we identify ZC3H12C as a conserved feature of dysfunctional T cells and show that its disruption enhances the durability and antitumor activity of engineered T cells. By integrating single-cell chromatin accessibility and transcriptomic profiling of human tumor-infiltrating lymphocytes (TILs), we identified the ZC3H12C locus as selectively remodeled in exhausted T cells. ZC3H12C induction is largely absent across acute T cell activation contexts, indicating regulation that is specific to chronic antigen-driven dysfunction. Genetic disruption of ZC3H12C improves T cell expansion, cytotoxicity, and expression of effector molecules during repeated in vitro stimulation, translating into enhanced tumor control in vivo across both T cell receptor (TCR) and chimeric antigen receptor (CAR) T cell therapy platforms. Improved efficacy is observed in hematologic, solid, and metastatic tumor models and is accompanied by increased T cell persistence. Further, ZC3H12C is enriched in clinical pre-infusion CAR T cell products associated with non-response. Together, these findings identify ZC3H12C as a T cell dysfunction-specific target to improve ACT performance.
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