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. Efficacy of chimeric antigen receptor (CAR)-T in solid tumors are limited by the antigen heterogeneity and tumor microenvironment (TME) induced exhaustion. The authors here manifested that Nr2f6-deficient CAR-T cells have superior anti-tumor effect compared with traditional CAR-T cells, which is associated with enhanced cytotoxic function, followed by durable response due to epitope spreading.