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 T cell 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, as shown by protection in tumor re‑challenge experiments. Although infused CAR‑T cells disappear within 2 weeks, durable tumor control coincides with epitope spreading and secondary immune responses, likely via dendritic and other antigen‑presenting 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 loss and tumor heterogeneity, establishing NR2F6 inhibition as a promising CAR‑T engineering strategy for durable, antigen‑agnostic solid‑tumor immunotherapy.