组蛋白脱乙酰酶（HDAC）是一种通过改变蛋白质乙酰化水平来调节基因表达的蛋白酶，通常在肿瘤中异常激活。已批准的泛 HDAC 抑制剂 (HDACi) 已显示出治疗造血系统恶性肿瘤的临床益处。最近，HDAC 已成为抗肿瘤免疫的增强剂。然而，HDACs对肺腺癌（LUAD）肿瘤免疫微环境的影响及其潜在机制尚不清楚。采用皮下肿瘤C57BL/6J和BALB/c裸鼠进行体内治疗效果和机制研究。采用流式细胞术测量人CD8 T细胞与肿瘤细胞共培养后的毒性和耗竭，并确定肿瘤浸润CD8 T细胞的免疫表型。采用RNA测序、定量PCR、蛋白质印迹、ELISA、质谱、免疫共沉淀、染色质免疫沉淀和免疫组化等一系列实验技术来探讨其潜在的分子机制。泛HDACi伏立诺他（SAHA）促进CD8 T通过抑制 FGL1（新鉴定的 LAG-3 的主要配体）来调节 LUAD 中的细胞浸润和效应子功能。从机制上讲，SAHA 抑制 HDAC1（JAK1 的一种重要脱乙酰酶）的活性。这增加了 JAK1 在赖氨酸 1109 处的乙酰化水平，从而促进其蛋白酶体降解并随后减少 STAT3 驱动的 FGL1 转录。在免疫功能正常的 LUAD 小鼠模型中进一步探索了 SAHA 和抗 LAG-3 治疗的联合方案。与接受对照或单药治疗的小鼠相比，接受联合治疗的小鼠表现出较低的肿瘤负荷和优异的 CD8 T 细胞杀伤活性。我们的结果揭示了 HDACi SAHA 通过以下方式增强 CD8 T 细胞介导的抗肿瘤活性的新机制： HDAC1/JAK1/FGL1 轴，为 HDACis 和免疫疗法联合使用提供了理由。© 作者（或其雇主）2024。根据 CC BY-NC 允许重复使用。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

Histone deacetylase (HDAC), a kind of protease that regulates gene expression by modifying protein acetylation levels, is usually aberrantly activated in tumors. The approved pan-HDAC inhibitors (HDACi) have exhibited clinical benefits for hematopoietic malignancies. Recently, HDACis have emerged as enhancers of antitumor immunity. However, the effect of HDACs on the tumor immune microenvironment of lung adenocarcinoma (LUAD) and the underlying mechanism is largely unknown.C57BL/6J and BALB/c nude mice with subcutaneous tumors were used for in vivo therapeutic effects and mechanistic investigations. Flow cytometry was used to measure the toxicity and exhaustion of human CD8+T cells after co-culturing with tumor cells and to determine the immunophenotype of tumor-infiltrating CD8+T cells. A series of experimental techniques, including RNA sequencing, quantitative PCR, western blot, ELISA, mass spectrometry, co-immunoprecipitation, chromatin immunoprecipitation and immunohistochemistry, were used to explore the underlying molecular mechanism.The pan-HDACi vorinostat (SAHA) promoted CD8+T cell infiltration and effector function in LUAD through suppressing FGL1, a newly identified major ligand of LAG-3. Mechanistically, SAHA inhibited the activity of HDAC1, an essential deacetylase of JAK1. This increased the acetylation level of JAK1 at lysine 1109, thus promoting its proteasomal degradation and subsequently reducing STAT3-driven FGL1 transcription. The combination regimen of SAHA and anti-LAG-3 therapy was further explored in an immunocompetent LUAD mouse model. Compared with those receiving control or single agent treatments, mice receiving combination therapy exhibited a lower tumor burden and superior CD8+T-cell-killing activity.Our results revealed a novel mechanism by which the HDACi SAHA potentiates CD8+T-cell-mediated antitumor activity through the HDAC1/JAK1/FGL1 axis, providing a rationale for the combined use of HDACis and immunotherapy.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.