Targeting Mitochondrial Metabolic Reprogramming: Reversing CD8⁺ T Cell Exhaustion and Improving Cancer Immunotherapy Response
DOI:
https://doi.org/10.63808/bm.v2i1.531Keywords:
Immunometabolism, Mitochondrial metabolic reprogramming, CD8⁺ T cell exhaustion, Cancer immunotherapy, Immune checkpoint inhibitors, PGC-1αAbstract
This study explores the reversal effect of targeting mitochondrial metabolic reprogramming on CD8⁺ T cell exhaustion within the tumor microenvironment and its synergistic mechanism when combined with immune checkpoint blockade therapy. B16-OVA melanoma and LLC lung cancer tumor-bearing mouse models were established. Using single-cell RNA sequencing, metabolic flux analysis, Seahorse cellular energy metabolism assay, and flow cytometry, we compared the mitochondrial function, metabolic characteristics, and exhaustion phenotypes of tumor-infiltrating CD8⁺ T cells with CD8⁺ T cells from the spleen/draining lymph nodes. By pharmacologically activating or overexpressing genes to intervene in the PGC-1α-mediated mitochondrial biogenesis pathway, we evaluated CD8⁺ T cell mitochondrial membrane potential, ROS levels, ATP production, oxygen consumption rate, and the ability to secrete IFN-γ, TNF-α, and Granzyme B. Further, combined treatment with anti-PD-1 was applied to observe tumor growth, survival, and the composition of tumor-infiltrating lymphocytes. Tumor-infiltrating CD8⁺ T cells exhibited reduced mitochondrial membrane potential, accumulated ROS, decreased oxygen consumption rate and ATP production, and showed increased expression of PD-1, TIM-3, LAG-3, and TOX, suggesting that metabolic dysfunction is closely related to T cell exhaustion. Targeting mitochondrial metabolic reprogramming can restore mitochondrial adaptability of CD8⁺ T cells, enhance their proliferation, cytokine secretion, and cytotoxicity, while reducing expression of exhaustion-associated molecules. The combination of this intervention with anti-PD-1 antibody significantly inhibited tumor growth, extended survival in tumor-bearing mice, and increased the proportion of stem-like/effector memory CD8⁺ T cells in tumors. Mitochondrial metabolic reprogramming is a key regulatory node for reversing CD8⁺ T cell exhaustion. Targeting this pathway can remodel the tumor immune microenvironment and enhance the response to immune checkpoint therapy, providing a potential new strategy for cancer immunotherapy.
References
[1] Bengsch, B., Johnson, A. L., Kurachi, M., et al. (2016). Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8+ T cell exhaustion. Immunity, 45(2), 358-373. https://doi.org/10.1016/j.immuni.2016.07.008
[2] Blank, C. U., Haining, W. N., Held, W., et al. (2019). Defining ‘T cell exhaustion’. Nat Rev Immunol, 19(11), 665-674. https://doi.org/10.1038/s41577-019-0221-9
[3] Buck, M. D., O’Sullivan, D., Klein Geltink, R. I., et al. (2016). Mitochondrial dynamics controls T cell fate through metabolic programming. Cell, 166(1), 63-76. https://doi.org/10.1016/j.cell.2016.05.035
[4] Chamoto, K., Chowdhury, P. S., Kumar, A., et al. (2017). Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity. Proc Natl Acad Sci U S A, 114(5), E761-E770. https://doi.org/10.1073/pnas.1620433114
[5] Dumauthioz, N., Tschumi, B., Wenes, M., et al. (2021). Enforced PGC-1α expression promotes CD8 T cell fitness, memory formation and antitumor immunity. Cell Mol Immunol, 18(7), 1761-1771. https://doi.org/10.1038/s41423-020-0365-3
[6] Handschin, C., & Spiegelman, B. M. (2006). Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr Rev, 27(7), 728-735. https://doi.org/10.1210/er.2006-0037
[7] Hashimoto, M., Kamphorst, A. O, Im, S. J., et al. (2018). CD8 T cell exhaustion in chronic infection and cancer: opportunities for interventions. Annu Rev Med, 69, 301-318. https://doi.org/10.1146/annurev-med-012017-043208
[8] Jenkins, R. W., Barbie, D. A., & Flaherty, K. T. (2018). Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer, 118(1), 9-16. https://doi.org/10.1038/bjc.2017.434
[9] Liu, G, Wang J, & An L. (2026a). Gut microbiota-derived butyrate induces trained immunity in intestinal macrophages to potentiate antitumor immunity. Biology and Medical Engineering, 2(1). https://doi.org/10.63808/bm.v2i1.523
[10] Liu, G. (2026). Tumor microenvironment: composition, dynamic evolution, and its significance in cancer treatment. Journal of Cancer Insights, 1(1). https://doi.org/10.66128/jci202601.1
[11] Liu, G., Wang, J., & An, L. (2026b). Mitochondrial DNA sensing reshapes the tumor immune microenvironment via cooperative cGAS-STING activation and ferroptosis. Global Health Care, 2(1). https://doi.org/10.63808/ghc.v2i1.524
[12] Liu, G., Wang, J., & Zhu, J. (2026c). Explainable spatial AI analyzes tumor-immune interactions to predict immunotherapy outcomes and identify new targets. Intelligent & Human Futures, 2(3). https://doi.org/10.63808/ihf.v2i3.510
[13] Liu, G., Wang, J., & Zhu, J. (2026d). Using multimodal foundational models to predict neoantigen immunogenicity and vaccine effectiveness across different tumor types. Global Health Care, 2(3). https://doi.org/10.63808/ghc.v2i3.498
[14] McLane, L. M., Abdel-Hakeem, M. S., & Wherry, E. J. (2019). CD8 T cell exhaustion during chronic viral infection and cancer. Annu Rev Immunol, 37, 457-495. https://doi.org/10.1146/annurev-immunol-041015-055318
[15] Miller, B. C., Sen, D. R., Al Abosy, R., et al. (2019). Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol, 20(3), 326-336. https://doi.org/10.1038/s41590-019-0312-6
[16] Patsoukis, N., Bardhan, K., Chatterjee, P., et al. (2015). PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun, 6, 6692. https://doi.org/10.1038/ncomms7692
[17] Pearce, E. L., Poffenberger, M. C., Chang, C. H., & Jones, R. G. (2013). Fueling immunity: insights into metabolism and lymphocyte function. Science, 342(6155), 1242454. https://doi.org/10.1126/science.1242454
[18] Sade-Feldman, M., Yizhak, K., Bjorgaard, S. L., et al. (2018). Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell, 175(4), 998-1013.e20. https://doi.org/10.1016/j.cell.2018.10.038
[19] Scharping, N. E., Menk, A. V., Moreci, R. S., et al. (2016). The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity, 45(2), 374-388. https://doi.org/10.1016/j.immuni.2016.07.009
[20] Scharping, N. E., Rivadeneira, D. B., Menk, A. V., Vignali, P. D. A., Ford, B. R., Rittenhouse, N. L., Peralta, R., Wang, Y., Wang, Y., DePeaux, K., Poholek, A. C., & Delgoffe, G. M. (2021). Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat Immunol, 22(2), 205-215. https://doi.org/10.1038/s41590-020-00834-9
[21] Sharma, P., Hu-Lieskovan, S., Wargo, J. A., & Ribas, A. (2017). Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell, 168(4), 707-723. https://doi.org/10.1016/j.cell.2017.01.017
[22] Siddiqui, I., Schaeuble, K., Chennupati, V., et al. (2019). Intratumoral Tcf1+PD-1+CD8+ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity, 50(1), 195-211.e10. https://doi.org/10.1016/j.immuni.2018.12.021
[23] Thommen, D. S., & Schumacher, T. N. (2018). T cell dysfunction in cancer. Cancer Cell, 33(4), 547-562. https://doi.org/10.1016/j.ccell.2018.03.012
[24] Topalian, S. L., Drake, C. G., & Pardoll, D. M. (2015). Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell, 27(4), 450-461. https://doi.org/10.1016/j.ccell.2015.03.001
[25] van der Windt, G. J., Everts, B., Chang, C. H., et al. (2012). Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity, 36(1), 68-78. https://doi.org/10.1016/j.immuni.2011.12.007
[26] Vardhana, S. A., Hwee, M. A., Berisa, M., et al. (2020). Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen. Nat Immunol, 21(9), 1022-1033. https://doi.org/10.1038/s41590-020-0725-2
[27] Wherry, E. J., & Kurachi, M. (2015). Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol, 15(8), 486-499. https://doi.org/10.1038/nri3862
[28] Yu, Y. R., Imrichova, H., Wang, H., et al. (2020). Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion. Nat Immunol, 21(12), 1540-1551. https://doi.org/10.1038/s41590-020-0793-3
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Gang Liu, Jia Wang, Alena Mikalaeuna Vasiukevich, Biao Feng, Liqiang An
This work is licensed under a Creative Commons Attribution 4.0 International License.