NR2F6 deletion revives CAR-T cell function and induces antigen-agnostic immune memory in solid tumors
CAR-T cell therapy is effective in hematologic malignancies but remains challenging in solid tumors owing to antigen heterogeneity and tumor microenvironment-induced exhaustion. Here, gene editing of the nuclear receptor NR2F6 restores CAR-T cell functionality, sustaining a TCF1⁺ progenitor-exhausted phenotype, enhancing metabolic fitness, and preserving cytotoxic potency under chronic antigen exposure. In immunocompetent models, Nr2f6-deficient CAR-T cells suppress solid tumor growth and induce robust, polyclonal host antitumor responses that persist after CAR-T clearance, as demonstrated by tumor re-challenge protection. Although infused CAR-T cells disappear within 2 weeks, durable tumor control coincides with epitope spreading and secondary immune responses, likely via dendritic cell reactivation. Protection against antigen-negative tumors and transferable immunity reveal a dual mode of direct cytotoxicity followed by durable immune reprogramming. This broadened host immunity may offset immune escape driven by antigen heterogeneity or loss, establishing NR2F6 inhibition as a promising CAR-T engineering strategy for durable, antigen-agnostic solid-tumor immunotherapy.
Authors
- Victoria Klepsch (ORCID: https://orcid.org/0000-0003-4146-4664)
- Dominik Humer (ORCID: https://orcid.org/0009-0008-2167-9346)
- Sebastian Peer (ORCID: https://orcid.org/0000-0002-4372-5365)
- Ira Skvortsova (ORCID: https://orcid.org/0000-0001-8993-611X)
- Gottfried Baier (ORCID: https://orcid.org/0000-0002-2085-8325)
- Thomas Gruber (ORCID: https://orcid.org/0000-0002-5796-7090)
- Niκolaus Thuille (ORCID: https://orcid.org/0000-0002-2253-3946)
- Kerstin Siegmund (ORCID: https://orcid.org/0000-0002-3654-1170)
- Jiří Koutník (ORCID: https://orcid.org/0000-0003-0904-0968)
- Viana Wille
- Dragana Savic (ORCID: https://orcid.org/0000-0001-5196-4676)
- Sieghart Sopper (ORCID: https://orcid.org/0000-0003-2265-1974)
- Gabriel Diem (ORCID: https://orcid.org/0000-0002-8737-005X)
- Dietmar Rieder (ORCID: https://orcid.org/0000-0003-1754-690X)
- Tajana Sajinovic
- Wilfried Posch
- Krogsdam Anne
- Sebastian Kobold
- Viktor Lang
- Isabel Hölzl
- Zlatko Trajanoski
- Dominik Wolf
- Anna Fürst
- Daniel Schreiber
Institutions
- Innsbruck Medical University (AT)
- German Cancer Research Center (DE)
- Universität Innsbruck (AT)
- LMU Klinikum (DE)
- Tyrolean Cancer Research Institute (AT)
- München Klinik (DE)
- Technical University of Munich (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-02-27
- DOI
- https://doi.org/10.1038/s41467-026-69796-0
- Citations
- 1
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 24.20
Funders
- Österreichischen Akademie der Wissenschaften
- Austrian Science Fund
- Bayerische Forschungsstiftung