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T Cell Dysfunction and Exhaustion in Cancer
Open accessAbstract
Tumor immunotherapy is a promising therapeutic strategy for patients with advanced cancers. T cells are key mediators of antitumor function that specifically recognize and react to tumor-expressing antigens and have proven critical for cancer immunotherapy. However, T cells are not as effective against cancer as expected. This is partly because T cells enter a dysfunctional or exhausted state, which is characterized by sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory T cells. T cell dysfunction induces the out of control of tumors. Recently, T cell dysfunction has been investigated in many experimental and clinical settings. The molecular definition of T cell dysfunction and the underlying causes of the T cell dysfunction has been advanced regardless of the fact that the pathways involved are not well elucidated, which proposing promising therapeutic opportunities in clinic. In this review, we will discuss the recent advances in the molecular mechanisms that affect TME and induce T cell dysfunction, and the development of promising immunotherapies to counteract the mechanisms of tumor-induced T cell dysfunction. Better understanding these underlying mechanisms may lead to new strategies to improve the clinical outcome of patients with cancer.
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“T cell senescence is irreversible, as opposed to their anergy and exhaustion, both of which are considered reversible [31, 38–40].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [40]
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“In the light of mitochondrial dysfunction in HCC, expression profiles of mitoribosomal genes can be considered as critical biomarkers of disease severity and progression in HCC patients.”
Ao, Z., Wu, Z., Cai, H., Hu, L., Li, X., Kaurich, C., Chang, J., Gu, M., Liang Cheng, C., Lü, X., et al. (2022) · Advanced Science · doi:10.1002/advs.202201478 · Cited by 40
Self-assembling peptides as immunomodulatory biomaterials
Hernández, A., Hartgerink, J. D., & Young, S. W. (2023) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2023.1139782 · Cited by 39
“A faster release of anti-TNF-α was achieved due to protein diffusion through the KLD2R hydrogel, while the slower release of HGF was due to a combination of heparin-binding affinity and molecular diffusion.”
BackgroundInfluentialWang, S., Kuai, Y., Lin, S., Li, L., Gu, Q., Zhang, X., Li, X., He, Y., Chen, S., Xia, X., et al. (2023) · BMC Medicine · doi:10.1186/s12916-023-02791-0 · Cited by 35
Self-citationFluorogenic Granzyme A Substrates Enable Real‐Time Imaging of Adaptive Immune Cell Activity
Cheng, Z., Thompson, E. J., Mendive‐Tapia, L., Scott, J. I., Benson, S., Kitamura, T., Senan‐Salinas, A., Samarakoon, Y., Roberts, E. W., Arias, M. A., et al. (2022) · Angewandte Chemie International Edition · doi:10.1002/anie.202216142 · Cited by 36
Shen, C., Zhang, Z., Tian, Y., Li, F., Zhou, L., Jiang, W., Yang, L., Zhang, B., Wang, L., & Zhang, Y. (2021) · BMC Medicine · doi:10.1186/s12916-021-02161-8 · Cited by 39
Self-citationReprogramming the tumor microenvironment with biotechnology
Kim, M., Lee, N. K., Wang, C. J., Lim, J., Byun, M. J., Kim, T. P., Park, W., Park, D.-H., Kim, S.-N., & Park, C. G. (2023) · Biomaterials Research · doi:10.1186/s40824-023-00343-4 · Cited by 37
“The upregulation of immune checkpoints and conversion into transcriptional and metabolic molecules are considered T cell dysfunction [90].”
BackgroundShen, C., Liu, C., Zhang, Z., Yü, P., Shao, J., Tian, Y., Yu, W., Qin, G., Liu, S., Wang, L., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.680055 · Cited by 35
Self-citationSaliba, J., Coutaud, B., Makhani, K., Roth, N. E., Jackson, J., Park, J. Y., Gagnon, N., Costa, P., Jeyakumar, T., Bury, M., et al. (2022) · Oncogene · doi:10.1038/s41388-022-02192-2 · Cited by 36
“This is of interest as tumors infiltrated with exhausted T cells are considered hot tumors that are responsive to immune checkpoint inhibitor drugs aimed at reactivating the infiltrated T cells [57].”
BackgroundExploring immune checkpoint inhibitors: Focus on PD-1/PD-L1 axis and beyond
Aden, D., Zaheer, S., Sureka, N., Trisal, M., Chaurasia, J. K., & Zaheer, S. (2025) · Pathology - Research and Practice · doi:10.1016/j.prp.2025.155864 · Cited by 37
Brauneck, F., Haag, F., Woost, R., Wildner, N. H., Tolosa, E., Rissiek, A., Vohwinkel, G., Wellbrock, J., Bokemeyer, C., Wiesch, J. S. Z., et al. (2021) · OncoImmunology · doi:10.1080/2162402x.2021.1930391 · Cited by 34
“One of the most important features of T-cell dysfunction seem to be the co-expression of multiple inhibitory receptors.(40) We observed increased frequencies of the PD-1TIGITCD73CD8and CD39TIGITCD73CD8 T-cell subsets in PB and BM from patients with newly diagnosed and relapsed AML.”
BackgroundAnti‐tumour potential of PD‐L1 / PD ‐1 post‐translational modifications
Zhou, S., Zhu, J., Xu, J., Gu, B., Zhao, Q., Luo, C., Gao, Z., Chin, Y. E., & Cheng, X. (2022) · Immunology · doi:10.1111/imm.13573 · Cited by 38
“Binding with their ligands, they initiate negative co-stimulation signals during antigen presentation to T cells, thus preventing over-activation [6, 7].”
Backgroundvan Elsas, M. J., Labrie, C., Etzerodt, A., Charoentong, P., Thans, J. J. C. V. S., van Hall, T., & van der Burg, S. H. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-006433 · Cited by 36
Ma, R., Zhou, X., Zhai, X., Wang, C., Hu, R., Chen, Y., Shi, L., Fang, X., Liao, Y., Ma, L., et al. (2024) · Cell Proliferation · doi:10.1111/cpr.13591 · Cited by 33
“9,10,25 Additionally, gene sets associated with senescence, including ribosome and histone genes, showed no significant differences between HAGC and NAGC, although there was a slight reduction compared to healthy controls (Figure 4D and Supplementary Figure S4C).”
ResultTiragolumab and TIGIT: pioneering the next era of cancer immunotherapy
Ghasemi, K. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1568664 · Cited by 33
Peptide-Based Vaccines for Hepatocellular Carcinoma: A Review of Recent Advances
Charneau, J., Suzuki, T., Shimomura, M., Fujinami, N., & Nakatsura, T. (2021) · Journal of Hepatocellular Carcinoma · doi:10.2147/jhc.s291558 · Cited by 35
Immune Checkpoint Inhibitor Associated Myocarditis and Cardiomyopathy: A Translational Review
Wang, D., Bauersachs, J. K., & Berliner, D. (2023) · Biology · doi:10.3390/biology12030472 · Cited by 36
Co-Expression of miR155 or LSD1 shRNA Increases the Anti-Tumor Functions of CD19 CAR-T Cells
Zhang, J., Zhu, J., Zheng, G., Wang, Q., Li, X., Feng, Y., Shang, F., He, S., Jiang, Q., Shi, B., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2021.811364 · Cited by 34
Repolarization of Tumor-Infiltrating Myeloid Cells for Augmentation of CAR T Cell Therapies
Luo, W., Napoleon, J. V., Zhang, F., Lee, Y. G., Wang, B., Putt, K. S., & Low, P. S. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.816761 · Cited by 32
Therapy-induced shaping of the glioblastoma microenvironment: Macrophages at play
Erbani, J. M., Boon, M., & Akkari, L. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.05.003 · Cited by 35
B Cells in Breast Cancer Pathology
Li, M., Quintana, Á., Alberts, E., Hung, M. S., Boulat, V., Martı́, M., & Grigoriadis, A. E. (2023) · Cancers · doi:10.3390/cancers15051517 · Cited by 34
Kao, C., Charmsaz, S., Alden, S. L., Brancati, M., Li, H. L., Balaji, A., Munjal, K., Howe, K., Mitchell, S., Leatherman, J. M., et al. (2024) · Journal of Clinical Investigation · doi:10.1172/jci176567 · Cited by 33
CD8+ T Cells in SARS-CoV-2 Induced Disease and Cancer—Clinical Perspectives
Mortezaee, K., & Majidpoor, J. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.864298 · Cited by 34
Strategies to overcome myeloid cell induced immune suppression in the tumor microenvironment
Cao, J. H., Chow, L., & DOW, S. W. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1116016 · Cited by 34
Bi, C., Patel, J. S., & Liang, S. H. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c02151 · Cited by 30
Shao, J., Hou, L., Liu, J., Liu, Y., Ning, J., Zhao, Q., & Zhang, Y. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.661357 · Cited by 31
Self-citationO'Reilly, M. A., Wilson, W., Burns, D., Kühnl, A., Seymour, F., Uttenthal, B., Besley, C., Alajangi, R., Creasey, T., Paneesha, S., et al. (2024) · HemaSphere · doi:10.1002/hem3.87 · Cited by 29
“35 Although, the manufacture of brexu ‐ cel encompasses a T ‐ cell selection step to remove contaminating cells from the harvest material, it is conceivable that circulating MCL cells in the peripheral blood, namely the TME, may contribute to inherent T ‐ cell dysfunction and failure of expansion…”
BackgroundBrownlie, D., von Kries, A., Valenzano, G., Wild, N., Yilmaz, E., Säfholm, J., Al‐Ameri, M., Alici, E., Ljunggren, H., Schliemann, I., et al. (2023) · OncoImmunology · doi:10.1080/2162402x.2023.2233402 · Cited by 29
“While conventional intratumoral NK cell and T cell subsets are considered hypofunctional 19,20 , our results suggest that trNK cells are tumor target cell-responsive.”
Antibody Responses to COVID-19 Vaccination in Cancer: A Systematic Review
Güven, D. C., Şahin, T. K., Kılıçkap, S., & Uckun, F. M. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.759108 · Cited by 27
Obesity and adipose tissue impact on T-cell response and cancer immune checkpoint blockade therapy
Pasquarelli-do-Nascimento, G., Machado, S. A., de Carvalho, J. M. A., & Magalhães, K. G. (2022) · Immunotherapy Advances · doi:10.1093/immadv/ltac015 · Cited by 29
“The obese phenotype copes with T lymphocyte dysfunction, a state characterized by a hyporesponsive profile, associated with loss of effector, proliferative capacity, and reduced production of cytokines, TNF-α and IFN-γ, in conditions that can be classified as anergy or exhaustion [123].”
Background
Metadata
- Authors
- Zhang, Z., Liu, S., Zhang, B., Qiao, L., Zhang, Y., & Zhang, Y.
- Affiliations
- First Affiliated Hospital of Zhengzhou University (CN)
- Northwestern University (US)
- Loyola University Chicago (US)
- Venue
- Frontiers in Cell and Developmental Biology
- Publisher
- Frontiers Media SA
- Published
- 2020-02-11
- Volume
- 8
- Pages
- 17-17
- ISSN
- 2296-634X (ISSN-L)
- PMC
- PMC7027373
- OpenAlex
- W3006138994
- Cited by
- 385
- References
- 120
- Citations by year
- 2026: 39 · 2025: 52 · 2024: 70 · 2023: 64 · 2022: 65 · 2021: 60 · 2020: 34
- FWCI
- 5.99
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Cell and Developmental Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (U1804281, 81771781, 81702810, 81773060)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- T cell dysfunction, T cell exhaustion, cancer immunotherapy, tumor microenvironment, inhibitory receptors, antitumor immunity, immunotherapy resistance
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