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Metabolic modulation and immune checkpoint therapy: overcoming CD8⁺ T cell exhaustion in the tumor microenvironment
- 1 University of Birmingham, Birmingham, UK
* Author to whom correspondence should be addressed.
Abstract
CD8+ T cells play a crucial role in tumor immunotherapy, especially in immune checkpoint therapy, and therefore have become the focus of cancer research. However, although immune checkpoint treatment has shown some efficacy in clinical trials, its effect is still limited by tumor immune escape. Tumors weaken CD8+ T cell function by adapting to immune stress, while mechanisms such as metabolic reprogramming and regulation of immunosuppressive factors further reduce their anti-tumor activity. Based on existing research and data, this paper discusses CD8+ T cell exhaustion, immune checkpoint regulation (PD-1/CTLA-4), and tumor microenvironment metabolism, and summarizes strategies to enhance the effect of immunotherapy. Studies have shown that by inhibiting T cell exhaustion, blocking immune checkpoint signaling pathways, and optimizing metabolism, CD8+ T cell function can be significantly enhanced and the overall therapeutic effect can be improved. However, while metabolic intervention appears promising, its clinical feasibility and safety require further validation. This study provides a theoretical basis for optimizing T cell immunotherapy and provides new ideas for clinical treatment.
Keywords
tumour, T cell exhaustion, immunosuppression, immune checkpoint, metabolism
[1]. Jahan, T., & Munshi, S. U. (2024). CD8+ T cells as multitasking cells in immunotherapy: A review update. Bangladesh Journal of Medical Microbiology, 18(1), 50–5. https://doi.org/10.3329/bjmm.v18i1.77075
[2]. Hillen, T., Enderling, H., & Hahnfeldt, P. (2012). The Tumor Growth Paradox and Immune System-Mediated Selection for Cancer stem cells. Bulletin of Mathematical Biology, 75(1), 161–184. https://doi.org/10.1007/s11538-012-9798-x
[3]. Zhang, B., Liu, J., Mo, Y., Zhang, K., Huang, B., & Shang, D. (2024). CD8+ T cell exhaustion and its regulatory mechanisms in the tumor microenvironment: key to the success of immunotherapy. Frontiers in Immunology, 15. https://doi.org/10.3389/fimmu.2024.1476904
[4]. Li, H., Zhao, A., Li, M., Shi, L., Han, Q., & Hou, Z. (2022). Targeting T-cell metabolism to boost immune checkpoint inhibitor therapy. Frontiers in Immunology, 13. https://doi.org/10.3389/fimmu.2022.1046755
[5]. Angelin, A., Gil-De-Gómez, L., Dahiya, S., Jiao, J., Guo, L., Levine, M. H. (2017). FOXP3 reprograms T cell metabolism to function in Low-Glucose, High-Lactate environments. Cell Metabolism, 25(6), 1282-1293.e7. https://doi.org/10.1016/j.cmet.2016.12.018
[6]. Kumagai, S., Koyama, S., Itahashi, K., Tanegashima, T., Lin, Y. T., Togashi, Y. (2022). Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell, 40(2), 201-218.e9. https://doi.org/10.1016/j.ccell.2022.01.001
[7]. Sakuishi, K., Apetoh, L., Sullivan, J. M., Blazar, B. R., Kuchroo, V. K., & Anderson, A. C. (2010). Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. The Journal of Experimental Medicine, 207(10), 2187–2194. https://doi.org/10.1084/jem.20100643
[8]. Chen, Z., Ji, Z., Ngiow, S. F., Manne, S., Cai, Z., Huang, A. C. (2019). TCF-1-Centered Transcriptional Network Drives an Effector versus Exhausted CD8 T Cell-Fate Decision. Immunity, 51(5), 840-855.e5. https://doi.org/10.1016/j.immuni.2019.09.013
[9]. Fischer, K., Hoffmann, P., Voelkl, S., Meidenbauer, N., Ammer, J., Edinger, M., et al. (2007). Inhibitory effect of tumor cell–derived lactic acid on human T cells. Blood, 109(9), 3812–3819. https://doi.org/10.1182/blood-2006-07-035972
[10]. Peralta, R., & Delgoffe, G. (2024). Dysfunction of exhausted T cells is enforced by MCT11-mediated lactate metabolism. The Journal of Immunology, 212(1_Supplement), 1394_5643. https://doi.org/10.4049/jimmunol.212.supp.1394.5643
[11]. Yu, T., Liu, Z., Tao, Q., Xu, X., Li, X., Li, Y. (2024). Targeting tumor-intrinsic SLC16A3 to enhance anti-PD-1 efficacy via tumor immune microenvironment reprogramming. Cancer Letters, 589, 216824. https://doi.org/10.1016/j.canlet.2024.216824
Cite this article
Zhang,H. (2025). Metabolic modulation and immune checkpoint therapy: overcoming CD8⁺ T cell exhaustion in the tumor microenvironment. Journal of Clinical Technology and Theory,3(1),19-22.
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