在慢性感染或癌症的持续抗原暴露下，T细胞功能失调。据认为，调控该衰竭状态的分子机制在感染和癌症中是共同的，尽管它们的微环境明显不同。在这里，我们发现NFAT5，一种缺乏AP-1结合位点的NFAT家族转录因子，在慢性感染和肿瘤背景下的疲惫CD8+ T细胞中高度表达，但在肿瘤诱导的CD8+ T细胞衰竭中有选择性需求。在CD8+ T细胞中过表达NFAT5降低了肿瘤控制能力，而NFAT5的删除通过促进积累具有降低TOX和PD-1表达及产生更多细胞因子，如IFNɣ和TNF的肿瘤特异性CD8+ T细胞来改善肿瘤控制能力，与具有野生型NFAT5水平的细胞相比，尤其出现在前体疲惫PD-1+TCF1+TIM-3-CD8+ T细胞中。NFAT5在淋巴细胞性脑膜炎病毒克隆13的慢性感染期间并不促进T细胞衰竭。NFAT5的表达受到TCR触发的诱导，但其转录活性特异于肿瘤微环境，并且需要高渗透性。因此，NFAT5以一种选择性的方式促进CD8+ T细胞的衰竭。© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

Persistent exposure to antigen during chronic infection or cancer renders T cells dysfunctional. The molecular mechanisms regulating this state of exhaustion are thought to be common in infection and cancer, despite obvious differences in their microenvironments. Here we found that NFAT5, an NFAT family transcription factor that lacks an AP-1 docking site, was highly expressed in exhausted CD8+ T cells in the context of chronic infections and tumors but was selectively required in tumor-induced CD8+ T cell exhaustion. Overexpression of NFAT5 in CD8+ T cells reduced tumor control, while deletion of NFAT5 improved tumor control by promoting the accumulation of tumor-specific CD8+ T cells that had reduced expression of the exhaustion-associated proteins TOX and PD-1 and produced more cytokines, such as IFNɣ and TNF, than cells with wild-type levels of NFAT5, specifically in the precursor exhausted PD-1+TCF1+TIM-3-CD8+ T cell population. NFAT5 did not promote T cell exhaustion during chronic infection with clone 13 of lymphocytic choriomeningitis virus. Expression of NFAT5 was induced by TCR triggering, but its transcriptional activity was specific to the tumor microenvironment and required hyperosmolarity. Thus, NFAT5 promoted the exhaustion of CD8+ T cells in a tumor-selective fashion.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.