免疫检查点阻断（ICB）疗法在微卫星不稳定（MSI）子宫内膜癌（EC）治疗中显示出临床疗效，其关键机制是逆转T细胞疲劳和恢复抗肿瘤免疫力。在这里，我们证明了转录因子19（TCF19）是癌症基因组图谱（TCGA）-EC队列中MSI和微卫星稳定（MSS）患者之间最显著差异表达的基因之一，与预后不良和免疫疲劳标记相关。具体地，TCF19在MSI EC中明显升高，进而促进三分体结构域含有14（TRIM14）的转录，并与TANK结合蛋白激酶1（TBK1）-干扰素调节因子3（IRF3）-干扰素β（IFN-β）通路的过度活化信号相关。TCF19-TRIM14轴促进非免疫背景下的肿瘤性，而下游增强的IFN-β分泌通过细胞分化重编程促进CD8+ T细胞疲劳。最后，使用人源模型，我们展示了TCF19抑制与ICB疗法相结合能够更有效地对抗肿瘤反应。总之，我们的研究表明，靶向TCF19是缓解CD8+ T细胞疲劳并与ICB在肿瘤治疗中协同作用的一种有效策略。此文章版权归2023年作者所有，由Elsevier公司发表，保留所有权利。

Immune checkpoint blockade (ICB) therapies display clinical efficacy in microsatellite instable (MSI) endometrial cancer (EC) treatment, the key mechanism of which is reversing T cell exhaustion and restoration of anti-tumor immunity. Here, we demonstrate that transcription factor 19 (TCF19), one of the most significantly differentially expressed genes between MSI and microsatellite stable (MSS) patients in The Cancer Genome Atlas (TCGA)-EC cohort, is associated with poor prognosis and immune exhaustion signature. Specifically, TCF19 is significantly elevated in MSI EC, which in turn promotes tripartite motif-containing 14 (TRIM14) transcription and correlates with hyperactive signaling of the TANK-binding kinase 1 (TBK1)-interferon regulatory factor 3 (IRF3)-interferon β (IFN-β) pathway. The TCF19-TRIM14 axis promotes tumorigenicity under non-immunological background, and the enhanced downstream secretion of IFN-β facilitates CD8+ T cell exhaustion through cell differentiation reprogramming. Finally, using humanized models, we show that a combination of TCF19 inhibition and ICB therapy demonstrates more effective anti-tumor responses. Together, our study indicates that targeting TCF19 is a potent strategy for alleviating CD8+ T cell exhaustion and synergizing with ICB in tumor treatment.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.