Exhaustion and senescence: two crucial dysfunctional states of T cells in the tumor microenvironment

Zhao, Yangjing; Shao, Qixiang; Peng, Guangyong

doi:10.1038/s41423-019-0344-8

Cited by 389Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

Exhaustion and senescence: two crucial dysfunctional states of T cells in the tumor microenvironment

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Zhao, Yangjing, Shao, Qixiang, Peng, Guangyong·2020·Cellular & Molecular Immunology

DOI 10.1038/s41423-019-0344-8PMC PMC6952436

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Abstract

The failure of a massive influx of tumor-infiltrating T lymphocytes to eradicate tumor cells in the tumor microenvironment is mainly due to the dysfunction of T cells hyporesponsive to tumors. T-cell exhaustion and senescence induced by malignant tumors are two important dysfunctional states that coexist in cancer patients, hindering effective antitumor immunity and immunotherapy and sustaining the suppressive tumor microenvironment. Although exhausted and senescent T cells share a similar dysfunctional role in antitumor immunity, they are distinctly different in terms of generation, development, and metabolic and molecular regulation during tumor progression. Here, we discuss the unique phenotypic and functional characteristics of these two types of dysfunctional T cells and their roles in tumor development and progression. In addition, we further discuss the potential molecular and metabolic signaling pathways responsible for the control of T-cell exhaustion and senescence in the suppressive tumor microenvironment. Understanding these critical and fundamental features should facilitate rethinking the unresponsiveness to current immunotherapies in clinical patients and lead to further development of novel and effective strategies that target different types of dysfunctional T cells to enhance cancer immunotherapy.

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T cell senescence is irreversible, whereas anergy and exhaustion are considered reversible.
“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 [39]

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Authors: Zhao, Y., Shao, Q., & Peng, G.
Affiliations: Jiangsu University (CN)
Saint Louis University (US)
Corresponding author: Peng, Guangyong
ORCID: Zhao, Yangjing
Shao, Qixiang
Peng, Guangyong
Venue: Cellular & Molecular Immunology
Publisher: Springer Science and Business Media LLC
Published: 2019-12-18
Volume: 17
Issue: 1
Pages: 27-35
ISSN: 1672-7681 (ISSN-L)
2042-0226
DOI: 10.1038/s41423-019-0344-8
PMC: PMC6952436
OpenAlex: W2995437528
Cited by: 382
References: 140
Citations by year: 2026: 39 · 2025: 90 · 2024: 70 · 2023: 59 · 2022: 61 · 2021: 45 · 2020: 18
FWCI: 2.95
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Cellular and Molecular Immunology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: American Cancer Society (RSG-10-160-01-LIB)
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 exhaustion, T cell senescence, tumor-infiltrating T cells, tumor microenvironment, antitumor immunity, immunotherapy resistance, T cell metabolism, metabolic signaling pathways, cancer immunotherapy
MeSH terms: Animals, Humans, Immunotherapy, Neoplasms, T-Lymphocytes, Lymphocytes, Tumor-Infiltrating, Cellular Senescence, Tumor Microenvironment

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Exhaustion and senescence: two crucial dysfunctional states of T cells in the tumor microenvironment

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