组蛋白赖氨酸乳酰化（Kla）是一种翻译后修饰，其在肿瘤免疫逃逸中的作用仍不清楚。在这里，我们发现组蛋白乳酰化增加与头颈鳞状细胞癌（HNSCC）免疫治疗反应不佳相关。 H3K9la 被鉴定为 HNSCC 中的特定修饰位点。通过靶标切割和标记分析，白细胞介素 11 (IL-11) 被鉴定为 H3K9la 的下游调控基因。 IL-11 通过 CD8 T 细胞中的 JAK2/STAT3 信号转导转录激活免疫检查点基因。此外，IL-11 过度表达会促进体内肿瘤进展和 CD8 T 细胞功能障碍。此外，IL11 敲低可逆转乳酸诱导的 CD8 T 细胞耗竭，胆固醇修饰的 siIL11 可恢复 CD8 T 细胞杀伤活性并增强免疫治疗功效。临床上，H3K9la 与 IL-11 表达和患者不利的免疫治疗反应呈正相关。这项研究揭示了组蛋白乳酰化在免疫逃逸中的关键作用，为 HNSCC 的免疫治疗策略提供了见解。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Histone lysine lactylation (Kla) is a post-translational modification, and its role in tumor immune escape remains unclear. Here, we find that increased histone lactylation is associated with poor response to immunotherapy in head and neck squamous cell carcinoma (HNSCC). H3K9la is identified as a specific modification site in HNSCC. Using cleavage under targets and tagmentation analyses, interleukin-11 (IL-11) is identified as a downstream regulatory gene of H3K9la. IL-11 transcriptionally activates immune checkpoint genes through JAK2/STAT3 signaling in CD8+ T cells. Additionally, IL-11 overexpression promotes tumor progression and CD8+ T cell dysfunction in vivo. Moreover, IL11 knockdown reverses lactate-induced CD8+ T cell exhaustion, and cholesterol-modified siIL11 restores CD8+ T cell killing activity and enhances immunotherapy efficacy. Clinically, H3K9la positively correlates with IL-11 expression and unfavorable immunotherapy responses in patients. This study reveals the crucial role of histone lactylation in immune escape, providing insights into immunotherapy strategies for HNSCC.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.