Research on the Mechanism by which Lactate Receptor GPR81 Mediates Differential Regulation of Immune Cell Subsets to Promote Tumor Immunosuppression
Main Article Content
Keywords
lactate, GPR81, tumor immune microenvironment, immune cell subsets, immunosuppression
Abstract
G protein-coupled receptor 81 (GPR81) is a lactate receptor that is upregulated in various malignant tumors. The specific mechanism by which it mediates immunosuppression in the tumor microenvironment has not been fully elucidated. This article systematically reviews the research progress on the activation of tumor cells by lactic acid and the differential regulation of GPR81 on the surface of immune cells by various immune cell subpopulations, thereby promoting tumor immune escape. Lactic acid activates GPR81 on tumor cells to upregulate the expression of a variety of inhibitory molecules, thereby inhibiting CD8⁺T cell function and promoting the recruitment of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). It binds to GPR81 on the surface of immune cells to inhibit the antigen presentation function of dendritic cells (DCs), polarizes macrophages toward the M2 type, and induces MDSCs to express immunosuppressive mediators. The above regulatory functions ultimately inhibit anti-tumor immunity. In-depth elucidation of the immune cell regulatory network mediated by GPR81 will provide an important theoretical basis for the development of combined immunotherapy strategies targeting the lactate signaling pathway.
References
- [1]Ji, X., & Xia, L. (2025). Lactate and lactylation in cancer: Drivers of immune suppression and microenvironmental reprogramming. Experimental Hematology & Oncology, 14(1), 128. https://doi.org/10.1186/s40164-025-00719-3.
- [2]Certo, M., Llibre, A., Lee, W., & Mauro, C. (2022). Understanding lactate sensing and signalling. Trends in Endocrinology and Metabolism, 33(10), 722–735. https://doi.org/10.1016/j.tem.2022.07.004.
- [3]Ishihara, S., Hata, K., Hirose, K., Okui, T., Toyosawa, S., Uzawa, N., Nishimura, R., & Yoneda, T. (2022). The lactate sensor GPR81 regulates glycolysis and tumor growth of breast cancer. Scientific Reports, 12(1), 6261. https://doi.org/10.1038/s41598-022-10143-w.
- [4]Xie, Q., Zhu, Z., He, Y., Zhang, Z., Zhang, Y., Wang, Y., Luo, J., Peng, T., Cheng, F., Gao, J., Cao, Y., Wei, H., & Wu, Z. (2020). A lactate-induced Snail/STAT3 pathway drives GPR81 expression in lung cancer cells. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1866(1), 165576. https://doi.org/10.1016/j.bbadis.2019.165576.
- [5]Zuo, S., Dong, J., Dong, Y., Fu, C., Li, X., Zhao, B., Wang, L., Zhang, Y., Kong, L., Yang, T., & Chen, L. (2026). SLC16A3-induced lactate remodeling drives immune evasion in clear cell renal cell carcinoma via an autocrine GPR81-ERK-c-MYC feedback loop. Balkan Medical Journal, 43(8), 434–448. https://doi.org/10.4274/balkanmedj.galenos.2026.2026-1-247.
- [6]Brown, T. P., Bhattacharjee, P., Ramachandran, S., Sivaprakasam, S., Ristic, B., Sikder, M. O. F., & Ganapathy, V. (2020). The lactate receptor GPR81 promotes breast cancer growth via a paracrine mechanism involving antigen-presenting cells in the tumor microenvironment. Oncogene, 39(16), 3292–3304. https://doi.org/10.1038/s41388-020-1216-5.
- [7]Manoharan, I., Prasad, P. D., Thangaraju, M., & Manicassamy, S. (2021). Lactate-dependent regulation of immune responses by dendritic cells and macrophages. Frontiers in Immunology, 12, 691134. https://doi.org/10.3389/fimmu.2021.691134.
- [8]He, J., Chai, X., Zhang, Q., Wang, Y., Wang, Y., Yang, X., Wu, J., Feng, B., Sun, J., Rui, W., Ze, S., Fu, Y., Zhao, Y., Zhang, Y., Zhang, Y., Liu, M., Liu, C., She, M., Hu, X., Ma, X., … Lu, W. (2025). The lactate receptor HCAR1 drives the recruitment of immunosuppressive PMN-MDSCs in colorectal cancer. Nature Immunology, 26(3), 391–403. https://doi.org/10.1038/s41590-024-02068-5.
- [9]Su, J., Mao, X., Wang, L., Chen, Z., Wang, W., Zhao, C., Li, G., Guo, W., & Hu, Y. (2024). Lactate/GPR81 recruits regulatory T cells by modulating CX3CL1 to promote immune resistance in a highly glycolytic gastric cancer. Oncoimmunology, 13(1), 2320951. https://doi.org/10.1080/2162402X.2024.2320951.
- [10]Stransky, N., & Huber, S. M. (2022). Comment on Chen et al. Dual blockade of lactate/GPR81 and PD-1/PD-L1 pathways enhances the anti-tumor effects of metformin. Biomolecules 2021, 11, 1373. Biomolecules, 12(4), 573. https://doi.org/10.3390/biom12040573.
Article Sidebar
This work is licensed under a Creative Commons Attribution 4.0 International License.