Li Jingyuan, Li Ziyi, Zhang Xiaoping, Zhang Hao, Tan Meihui, Tang Yao, Guo Shimeng, Ye Ting, Wang Jianyu, Li Jingyu
Chongqing Key Laboratory of Human Embryo Engineering and Precision Medicine, Center for Reproductive Medicine, Chongqing Health Center for Women and Children, Women and Children's Hospital of Chongqing Medical University, Chongqing, China; Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China; Molecular Biology Laboratory of Respiratory Disease, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
Molecular Biology Laboratory of Respiratory Disease, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
Cancer Lett. 2026 Feb 28;639:218227. doi: 10.1016/j.canlet.2025.218227. Epub 2025 Dec 19.
Breast cancer (BC) is the most common cancer in women, and triple-negative breast cancer (TNBC) is a highly aggressive and metastatic subtype, often characterized by metabolic dysregulation and immune evasion. Recent studies have linked enhanced glycolysis and metabolic reprogramming to TNBC malignancy. Histone lactylation, a novel modification derived from lactate, connects metabolism with gene regulation. This study unveils its pivotal role in promoting TNBC progression and reshaping the tumor immune microenvironment using single-cell genomics, multi-omics, and clinical cohorts. Glycolysis-related genes are enriched in TNBC cells, with elevated lactate dehydrogenase A (LDHA) correlating with poor prognosis and increased histone lactylation. Inhibiting glycolysis reduces histone lactylation, suppressing tumor growth and metastasis. Mechanistically, lactate-derived histone lactylation enhances chromatin accessibility and drives oncogene transcription. Additionally, histone lactylation cooperates with active transcription-associated histone marks, such as H3K27ac, to further promote chromatin accessibility, thereby reprogramming the tumor's epigenetic landscape. Site-specific lactylation at H3K9la, H3K14la and H3K18la regulates distinct malignant traits. Single-cell immune profiling reveals lactylation-dependent immune cell states, underscoring its role in immune modulation. Furthermore, glycolysis-driven histone lactylation in TNBC is closely associated with the modulation of tumor immune responses and the regulation of immune-related pathways. Overall, histone lactylation links metabolic reprogramming to gene regulation. By modulating tumor progression and immune responses, histone lactylation emerges as a promising therapeutic target for improving TNBC management and patient outcomes.
乳腺癌（BC）是女性中最常见的癌症，三阴性乳腺癌（TNBC）是一种高度侵袭性和转移性的亚型，其特征通常是代谢失调和免疫逃逸。最近的研究将糖酵解增强和代谢重编程与TNBC的恶性程度联系起来。组蛋白乳酸化是一种源自乳酸的新型修饰，它将代谢与基因调控联系起来。本研究使用单细胞基因组学、多组学和临床队列揭示了其在促进TNBC进展和重塑肿瘤免疫微环境中的关键作用。糖酵解相关基因在TNBC细胞中富集，乳酸脱氢酶A（LDHA）升高与预后不良和组蛋白乳酸化增加相关。抑制糖酵解可减少组蛋白乳酸化，抑制肿瘤生长和转移。从机制上讲，乳酸衍生的组蛋白乳酸化增强了染色质的可及性并驱动癌基因转录。此外，组蛋白乳酸化与活性转录相关的组蛋白标记（如H3K27ac）协同作用，进一步促进染色质的可及性，从而重新编程肿瘤的表观遗传景观。H3K9la、H3K14la和H3K18la位点特异性乳酸化调节不同的恶性特征。单细胞免疫分析揭示了乳酸化依赖性免疫细胞状态，强调了其在免疫调节中的作用。此外，TNBC中糖酵解驱动的组蛋白乳酸化与肿瘤免疫反应的调节和免疫相关途径的调控密切相关。总体而言，组蛋白乳酸化将代谢重编程与基因调控联系起来。通过调节肿瘤进展和免疫反应，组蛋白乳酸化成为改善TNBC管理和患者预后的有希望的治疗靶点。
