Zhou Sheng, Xiao Linmei, Hu Li, Zuo Fei, Wang Yuanhang, Fei Bojian, Dai Jialin, Zhou Xinyi
Department of Gastrointestinal Surgery, Affiliated Hospital of Jiangnan University, 1000 Hefeng Road, Wuxi, 214000, Jiangsu Province, China.
Department of General Surgery, The First Affiliated Hospital of Ningbo University, Ningbo, 315000, Zhejiang Province, China.
J Transl Med. 2025 Sep 2;23(1):989. doi: 10.1186/s12967-025-07013-0.
Cancer-associated fibroblasts (CAFs) can facilitate tumor progression through multiple approaches. Research indicates that CAFs in various tumors exhibit robust lactate metabolism, ultimately becoming the primary source of lactate in the tumor microenvironment. Emerging evidence has established that CAFs could orchestrate gastric cancer (GC) immune evasion. However, the potential role of CAFs-derived lactate in immunotherapy remains elusive.
In our research, CUT&Tag and transcriptome sequencing were employed to detect the target gene of histone lactylation. Co-immunoprecipitation, mass spectrometry analysis, and molecular docking, were utilized to explore the interactions between proteins. We performed cellular, animal, and organoid experiments to verify the mechanism.
We found that lactate secreted by CAFs was elevated, facilitating the lactylation of H3K18 in GC cells. As a target of H3K18la, ASPM played crucial roles in regulating the GC progression by promoting resistance to anti-PD-1. Mechanistically, ASPM promoted the transport of NCAPG from the nucleus to the cytoplasm by directly binding to it and then enhanced the deubiquitination of NCAPG mediated by BUB3, thereby increasing the expression of NCAPG. Furthermore, NCAPG targeted the SRC/STAT3 pathway and elevated PD-L1 expression. In addition, Daturilin has been preliminarily identified as a small-molecule inhibitor targeting NCAPG.
In conclusion, we have identified that CAFs-derived lactate promoted GC progression and clarified its mechanism, proposing the H3K18la-ASPM-NCAPG axis. Daturilin could enhance the therapeutic efficacy of anti-PD-1 treatment. This offers innovative perspectives on the complex role of CAFs in the TME and the influence of lactate on tumor progression.
癌症相关成纤维细胞（CAFs）可通过多种途径促进肿瘤进展。研究表明，各种肿瘤中的CAFs表现出旺盛的乳酸代谢，最终成为肿瘤微环境中乳酸的主要来源。新出现的证据表明，CAFs可协调胃癌（GC）的免疫逃逸。然而，CAFs衍生的乳酸在免疫治疗中的潜在作用仍不清楚。
在我们的研究中，采用CUT&Tag和转录组测序来检测组蛋白乳酸化的靶基因。利用免疫共沉淀、质谱分析和分子对接来探索蛋白质之间的相互作用。我们进行了细胞、动物和类器官实验来验证该机制。
我们发现CAFs分泌的乳酸升高，促进了GC细胞中H3K18的乳酸化。作为H3K18la的一个靶点，ASPM通过促进对抗PD-1的抗性在调节GC进展中发挥关键作用。机制上，ASPM通过直接与NCAPG结合促进其从细胞核转运到细胞质，然后增强BUB3介导的NCAPG去泛素化，从而增加NCAPG的表达。此外，NCAPG靶向SRC/STAT3途径并提高PD-L1表达。此外，陀罗碱已被初步鉴定为靶向NCAPG的小分子抑制剂。
总之，我们已经确定CAFs衍生的乳酸促进了GC进展并阐明了其机制，提出了H3K18la-ASPM-NCAPG轴。陀罗碱可增强抗PD-1治疗的疗效。这为CAFs在肿瘤微环境中的复杂作用以及乳酸对肿瘤进展的影响提供了创新观点。
