ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Cancer Cell Biology
Volume 13 - 2025 | doi: 10.3389/fcell.2025.1565993
Lactate modulates the function of myeloid-derived suppressor cells via Ten-Eleven-Translocation-2-mediated demethylation of glucocorticoidinducible kinase 1 in lung cancer model
Provisionally accepted
- 1Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, China
- 2Jiangsu University, Zhenjiang, China
- 3Jiangsu Cancer Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
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Background: Lactate has been shown to play an important immunosuppressive role in the tumor microenvironment (TME) and promote tumor progression through a variety of different mechanisms of action. Myeloid-derived suppressor cells (MDSCs) are important cells that play an immunosuppressive role in the TME. However, the underlying mechanism by which lactate regulates MDSCs remains unclear. This study aims to explore the molecular mechanism by which lactate regulates the immunosuppressive function of MDSCs in the TME, providing new ideas and targets for anti-tumor immunotherapy targeting MDSCs.Methods: This study used the Lewis lung carcinoma cell line to establish a subcutaneous lung cancer model; MDSCs were isolated from the spleens of these mice for subsequent experiments. Protein expression was analyzed by Western blot, mRNA expression by qRT-PCR, protein-DNA interactions by ChIP-qPCR, and DNA methylation by MSP-qPCR and BSP. Exploring the regulatory mechanism of CD38 on the immunosuppressive function of MDSCs by knockdown and overexpression techniques. Results: We found that compared with spleen-derived MDSCs (SP-MDSCs) of subcutaneous lung cancer model, tumor-derived MDSCs (T-MDSCs) had stronger immunosuppressive function. Lactate could promote the immunosuppressive function of MDSCs, significantly up-regulate the expression of serum and glucocorticoid-inducible kinase 1 (SGK1) in MDSCs. Further studies demonstrated that lactate could down-regulate the DNA methylation level of SGK1 by regulating the Ten-Eleven-Translocation-2 (TET2) and TET2 was closely related to the immunosuppressive function of MDSCs and the progression of tumors. Conclusions: Lactate can up-regulate the expression of SGK1 through demethylation mediated by TET2, enhancing the immunosuppressive function of MDSCs to promote tumor progression. It provides the effective therapeutic targets for anti-tumor therapy.
Keywords: lactate 1, MDSCs 2, TET23, SGK14, DNA methylation 5 lactate, MDSCs, SGK1, TET2
Received: 07 Feb 2025; Accepted: 08 Aug 2025.
Copyright: © 2025 Chu, Shen, Li, Shen, Zhang, Wang, Zhu, Wang and Ma. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jie Ma, Jiangsu University, Zhenjiang, China
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