Cited by 963Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyImmune Cell Function and Interaction

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TIM3 comes of age as an inhibitory receptor

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Wolf, Yochai, Anderson, Ana C., Kuchroo, Vijay K.·2020·Nature Reviews Immunology

DOI 10.1038/s41577-019-0224-6PMC PMC7327798

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Abstract

T cell immunoglobulin and mucin domain-containing protein 3 (TIM3), a member of the TIM family, was originally identified as a receptor expressed on interferon-γ-producing CD4+ and CD8+ T cells. Initial data indicated that TIM3 functioned as a 'co-inhibitory' or 'checkpoint' receptor, but due to the lack of a definable inhibitory signalling motif, it was also suggested that TIM3 might act as a co-stimulatory receptor. Recent studies have shown that TIM3 is part of a module that contains multiple co-inhibitory receptors (checkpoint receptors), which are co-expressed and co-regulated on dysfunctional or 'exhausted' T cells in chronic viral infections and cancer. Furthermore, co-blockade of TIM3 and programmed cell death 1 (PD1) can result in tumour regression in preclinical models and can improve anticancer T cell responses in patients with advanced cancers. Here, we highlight the developments in understanding TIM3 biology, including novel ligand identification and the discovery of loss-of-function mutations associated with human disease. In addition, we summarize emerging data from human clinical trials showing that TIM3 indeed acts as a 'checkpoint' receptor and that inhibition of TIM3 enhances the antitumour effect of PD1 blockade.

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Chisholm, J. D., & Kerr, W. G. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-29808-0.00039-x
Additional file 8 of Identification of a robust signature for clinical outcomes and immunotherapy response in gastric cancer: based on N6-methyladenosine related long noncoding RNAs
Han, T., Xu, D., Zhu, J., Li, J., Liu, L., & Deng, Y. (2021) · Figshare · doi:10.6084/m9.figshare.15179224
Additional file 5 of Identification of a robust signature for clinical outcomes and immunotherapy response in gastric cancer: based on N6-methyladenosine related long noncoding RNAs
Han, T., Xu, D., Zhu, J., Li, J., Liu, L., & Deng, Y. (2021) · Figshare · doi:10.6084/m9.figshare.15179215
Additional file 1 of Spatial features of specific CD103+CD8+ tissue-resident memory T cell subsets define the prognosis in patients with non-small cell lung cancer
Yang, G., Cai, S., Hu, M., Li, C., Yang, L., Zhang, W., Sun, J., Sun, F., Xing, L., & Sun, X. (2024) · Figshare · doi:10.6084/m9.figshare.26663506
Additional file 2 of Diffuse large B-cell lymphoma: the significance of CD8+ tumor-infiltrating lymphocytes exhaustion mediated by TIM3/Galectin-9 pathway
Zhu, Q., Yang, Y., Chen, K., Zhang, Q., Huang, Y., & Jian, S. (2024) · Figshare · doi:10.6084/m9.figshare.26682370
Additional file 7 of Identification of a robust signature for clinical outcomes and immunotherapy response in gastric cancer: based on N6-methyladenosine related long noncoding RNAs
Han, T., Xu, D., Zhu, J., Li, J., Liu, L., & Deng, Y. (2021) · Figshare · doi:10.6084/m9.figshare.15179221
Additional file 2 of Transcriptome sequencing and miRNA-mRNA network construction in exosome of macrophage M2 in stomach adenocarcinoma
Pan, D., Li, Z., Lin, X., & Li, L. (2023) · Figshare · doi:10.6084/m9.figshare.23590519
Additional file 1 of TLR7 agonist, DSP-0509, with radiation combination therapy enhances anti-tumor activity and modulates T cell dependent immune activation
Ota, Y., Inagaki, R., Nagai, Y., Hirose, Y., Murata, M., & Yamamoto, S. (2024) · Figshare · doi:10.6084/m9.figshare.26378059
Additional file 2 of Spatial features of specific CD103+CD8+ tissue-resident memory T cell subsets define the prognosis in patients with non-small cell lung cancer
Yang, G., Cai, S., Hu, M., Li, C., Yang, L., Zhang, W., Sun, J., Sun, F., Xing, L., & Sun, X. (2024) · Figshare · doi:10.6084/m9.figshare.26663509
Additional file 1 of DFNA5 regulates immune cells infiltration and exhaustion
Hu, J., Pei, W., Jiang, M., Huang, Y., Dong, F., Jiang, Z., Xu, Y., & Li, Z. (2022) · Figshare · doi:10.6084/m9.figshare.19313758
Additional file 12 of Identification of a robust signature for clinical outcomes and immunotherapy response in gastric cancer: based on N6-methyladenosine related long noncoding RNAs
Han, T., Xu, D., Zhu, J., Li, J., Liu, L., & Deng, Y. (2021) · Figshare · doi:10.6084/m9.figshare.15179200
Additional file 2 of TLR7 agonist, DSP-0509, with radiation combination therapy enhances anti-tumor activity and modulates T cell dependent immune activation
Ota, Y., Inagaki, R., Nagai, Y., Hirose, Y., Murata, M., & Yamamoto, S. (2024) · Figshare · doi:10.6084/m9.figshare.26378119
Additional file 3 of Transcriptome sequencing and miRNA-mRNA network construction in exosome of macrophage M2 in stomach adenocarcinoma
Pan, D., Li, Z., Lin, X., & Li, L. (2023) · Figshare · doi:10.6084/m9.figshare.23590522
Additional file 2 of Identification of a robust signature for clinical outcomes and immunotherapy response in gastric cancer: based on N6-methyladenosine related long noncoding RNAs
Han, T., Xu, D., Zhu, J., Li, J., Liu, L., & Deng, Y. (2021) · Figshare · doi:10.6084/m9.figshare.15179206
Additional file 10 of Identification of a robust signature for clinical outcomes and immunotherapy response in gastric cancer: based on N6-methyladenosine related long noncoding RNAs
Han, T., Xu, D., Zhu, J., Li, J., Liu, L., & Deng, Y. (2021) · Figshare · doi:10.6084/m9.figshare.15179194
Additional file 11 of Identification of a robust signature for clinical outcomes and immunotherapy response in gastric cancer: based on N6-methyladenosine related long noncoding RNAs
Han, T., Xu, D., Zhu, J., Li, J., Liu, L., & Deng, Y. (2021) · Figshare · doi:10.6084/m9.figshare.15179197
Additional file 3 of Identification of a robust signature for clinical outcomes and immunotherapy response in gastric cancer: based on N6-methyladenosine related long noncoding RNAs
Han, T., Xu, D., Zhu, J., Li, J., Liu, L., & Deng, Y. (2021) · Figshare · doi:10.6084/m9.figshare.15179209
Additional file 6 of Identification of a robust signature for clinical outcomes and immunotherapy response in gastric cancer: based on N6-methyladenosine related long noncoding RNAs
Han, T., Xu, D., Zhu, J., Li, J., Liu, L., & Deng, Y. (2021) · Figshare · doi:10.6084/m9.figshare.15179218
Additional file 9 of Identification of a robust signature for clinical outcomes and immunotherapy response in gastric cancer: based on N6-methyladenosine related long noncoding RNAs
Han, T., Xu, D., Zhu, J., Li, J., Liu, L., & Deng, Y. (2021) · Figshare · doi:10.6084/m9.figshare.15179227
Additional file 4 of TLR7 agonist, DSP-0509, with radiation combination therapy enhances anti-tumor activity and modulates T cell dependent immune activation
Ota, Y., Inagaki, R., Nagai, Y., Hirose, Y., Murata, M., & Yamamoto, S. (2024) · Figshare · doi:10.6084/m9.figshare.26753650
Additional file 1 of Diffuse large B-cell lymphoma: the significance of CD8+ tumor-infiltrating lymphocytes exhaustion mediated by TIM3/Galectin-9 pathway
Zhu, Q., Yang, Y., Chen, K., Zhang, Q., Huang, Y., & Jian, S. (2024) · Figshare · doi:10.6084/m9.figshare.26682367
Additional file 3 of TLR7 agonist, DSP-0509, with radiation combination therapy enhances anti-tumor activity and modulates T cell dependent immune activation
Ota, Y., Inagaki, R., Nagai, Y., Hirose, Y., Murata, M., & Yamamoto, S. (2024) · Figshare · doi:10.6084/m9.figshare.26753647
Additional file 1 of Newly diagnosed cardiovascular disease in patients treated with immune checkpoint inhibitors: a retrospective analysis of patients at an academic tertiary care center
Waheed, N., Fradley, M. G., DeRemer, D. L., Mahmoud, A., Shah, C., Langaee, T. Y., Lipori, G. P., March, K. L., Pepine, C. J., Cooper‐DeHoff, R. M., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14247680
Additional file 1 of Transcriptome sequencing and miRNA-mRNA network construction in exosome of macrophage M2 in stomach adenocarcinoma
Pan, D., Li, Z., Lin, X., & Li, L. (2023) · Figshare · doi:10.6084/m9.figshare.23590516
Additional file 4 of Identification of a robust signature for clinical outcomes and immunotherapy response in gastric cancer: based on N6-methyladenosine related long noncoding RNAs
Han, T., Xu, D., Zhu, J., Li, J., Liu, L., & Deng, Y. (2021) · Figshare · doi:10.6084/m9.figshare.15179212
Additional file 1 of Identification of a robust signature for clinical outcomes and immunotherapy response in gastric cancer: based on N6-methyladenosine related long noncoding RNAs
Han, T., Xu, D., Zhu, J., Li, J., Liu, L., & Deng, Y. (2021) · Figshare · doi:10.6084/m9.figshare.15179203
Human Immunodeficiency Virus–Associated Proteomic Signature of Myocardial Fibrosis and Incident Heart Failure
Peterson, T. E., Hahn, V. S., Moaddel, R., Zhu, M., Fan, J., De, S., Haberlen, S., Palella, F. J., Plankey, M. W., Bader, J. S., et al. (2026) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiag013
Tim-3 Expression in Duodenal Mucosa: The Role in the Pathogenesis and Diagnosis of Celiac Disease As An İmmune Checkpoint Molecule
Yılmaz, F., & Atay, K. (2026) · OSMANGAZİ JOURNAL OF MEDICINE · doi:10.20515/otd.1782586
TP53-mutated myelodysplastic syndromes and acute myeloid leukemia: a comprehensive overview of targeted approaches
Deshpande, S., Li, W. F., Song, J., Forsberg, M., Cerchione, C., Martinelli, G., & Konopleva, M. Y. (2026) · Frontiers in Oncology · doi:10.3389/fonc.2026.1735418
TGF-β regulated Tim-3 sustains macrophage phagocytic function and confers protection in Plasmodium yoelii NSM-infected mice
Xie, X., Liang, G., Chen, M., Lixin, L., Yuan, H., Chen, S., Lu, K., Peng, W., Xu, L., Xie, H., et al. (2026) · Parasites & Vectors · doi:10.1186/s13071-026-07287-3
TIM3 alleviates microglia-mediated neuroinflammation in neuropathic pain by negatively regulating glycolysis-driven NLRP3 inflammasome activation
Jiang, J. R., Li, Y., Zhang, M., Yin, C., Qi, Z., Xu, J., & Lu, C. (2026) · Acta Biochimica et Biophysica Sinica · doi:10.3724/abbs.2026034 · Cited by 1

Authors: Wolf, Y., Anderson, A. C., & Kuchroo, V. K.
Affiliations: Brigham and Women's Hospital (US)
Corresponding author: Kuchroo, Vijay K.
ORCID: Wolf, Yochai
Anderson, Ana C.
Kuchroo, Vijay K.
Venue: Nature Reviews Immunology
Publisher: Springer Science and Business Media LLC
Published: 2019-11-01
Volume: 20
Issue: 3
Pages: 173-185
ISSN: 1474-1733 (ISSN-L)
1474-1741
DOI: 10.1038/s41577-019-0224-6
PMC: PMC7327798
OpenAlex: W2985205513
Cited by: 959
References: 159
Citations by year: 2026: 98 · 2025: 140 · 2024: 191 · 2023: 160 · 2022: 183 · 2021: 142 · 2020: 44
FWCI: 8.75
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature reviews. Immunology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
National Cancer Institute (R01CA187975)
National Institute of Allergy and Infectious Diseases (P01AI073748, P01AI056299, P01AI039671)
National Institute of Neurological Disorders and Stroke (R01NS045937)
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 › Immune Cell Function and Interaction
Keywords: TIM-3, inhibitory receptors, co-inhibitory receptors, immune checkpoint, T cell exhaustion, loss-of-function mutations, antitumor immunity, chronic viral infection, cancer immunotherapy
MeSH terms: Hepatitis A Virus Cellular Receptor 2, Animals, Clinical Trials as Topic, Humans, Signal Transduction, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Programmed Cell Death 1 Receptor

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TIM3 comes of age as an inhibitory receptor

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