肿瘤细胞治疗研究
英文原题：NR2F6 deletion revives CAR-T cell function and induces antigen-agnostic immune memory in solid tumors.
尽管输注的 CAR-T 细胞在 2 周内即消失，但持久的肿瘤控制与表位扩展及继发性免疫反应相伴出现，可能通过树突状细胞再激活实现。
CAR-T 细胞疗法在血液系统恶性肿瘤中有效，但在实体瘤中仍面临挑战，原因在于抗原异质性和肿瘤微环境诱导的耗竭。在此，对核受体 NR2F6 进行基因编辑可恢复 CAR-T 细胞功能，维持 TCF1 祖细胞耗竭表型，增强代谢适应性，并在慢性抗原暴露下保持细胞毒性效力。在免疫健全模型中，Nr2f6 缺陷型 CAR-T 细胞可抑制实体瘤生长，并诱导强烈、多克隆的宿主抗肿瘤反应，且在 CAR-T 清除后仍持续存在，肿瘤再挑战保护实验证实了这一点。尽管输注的 CAR-T 细胞在 2 周内消失，但持久的肿瘤控制与表位扩展和继发性免疫反应同时出现，可能通过树突状细胞再激活介导。对抗原阴性肿瘤的保护作用以及可转移的免疫表明，其具有直接细胞毒性继以持久免疫重编程的双重模式。这种被拓宽的宿主免疫可能抵消由抗原异质性或抗原丢失驱动的免疫逃逸，从而确立 NR2F6 抑制作为一种有前景的 CAR-T 工程化策略，用于实现持久、不依赖抗原的实体瘤免疫治疗。
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.
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