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<p>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, <i>Nr2f6</i>-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.</p>

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NR2F6 deletion revives CAR-T cell function and induces antigen-agnostic immune memory in solid tumors

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月27日

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  • Dominik Humer,
  • Victoria Klepsch,
  • Dietmar Rieder,
  • Isabel Hölzl,
  • Daniel Schreiber,
  • Viktor Lang,
  • Jiří Koutník,
  • Sebastian Peer,
  • Tajana Sajinovic,
  • Viana Wille,
  • Anna Fürst,
  • Dragana Savic,
  • Gabriel Diem,
  • Wilfried Posch,
  • Ira-Ida Skvortsova,
  • Anne Krogsdam,
  • Sieghart Sopper,
  • Sebastian Kobold,
  • Zlatko Trajanoski,
  • Kerstin Siegmund,
  • Nikolaus Thuille,
  • Thomas Gruber,
  • Dominik Wolf,
  • Gottfried Baier

摘要

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.