Targeting ZC3H12C improves T cell persistence and antitumor function in adoptive T cell therapy
Year: 2026
Type: preprint
Abstract: 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.
Authors: Gayatri Kavishwar, Markus Perl, Christoph Heuser-Loy, Leonard Knoedler, Dhyani Shah, Fabio Mastrogiovanni, Konstantin Herfeld, Pedro Noronha, Manuela Kovács-Sautter, Maria Krieger, Stefan Loipfinger, Caio Raony Farina Silveira, Sascha Göttert, Roland Schelker, Luisa-Marie Becker, Timea Vadász, Carmen Gerlach, Gloria Lutzny-Geier, Luca Gattinoni, Hendrik Poeck, Christian Schmidl
Institutions: Leibniz Institute for Immunotherapy, University Hospital Regensburg, University of Bonn, University Hospital Bonn, Humboldt-Universität zu Berlin, Charité – Universitätsmedizin Berlin, Karolinska University Hospital, Karolinska Institutet, University of Regensburg, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7160283228