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The diversity of CD8+ T cell dysfunction in cancer and viral infection
- Lorenzo Galluzzi ORCID:orcid.org/0000-0003-2257-85001,
- Kellie N. Smith ORCID:orcid.org/0000-0002-6295-89302,3,
- Adrian Liston ORCID:orcid.org/0000-0002-6272-40854 &
- …
- Abhishek D. Garg ORCID:orcid.org/0000-0002-9976-99225
Nature Reviews Immunologyvolume 25, pages662–679 (2025)Cite this article
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Abstract
CD8+ T cells that are repeatedly exposed to antigenic stimulation, such as in the context of progressing neoplasms and chronic viral infections, acquire a dysfunctional or hypofunctional state that is generally known as exhaustion. There have been considerable efforts to develop therapeutic strategies that prevent exhaustion in these pathological scenarios, but there has been limited success. This may be because exhaustion is not the only source of T cell hypofunction in cancer and chronic viral infection. Here, we discuss the molecular and spatiotemporal mechanisms beyond exhaustion that underlie the inability of CD8+ T cells to eradicate malignant or chronically infected cells. We also propose a framework to enhance our understanding of these mechanisms — which include tolerization, anergy, senescence, cell death, exclusion and ignorance — with the ultimate aim of informing novel approaches to improve the clinical management of cancer and chronic viral infection.
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Acknowledgements
A.D.G. is supported by Research Foundation Flanders (Fundamental Research grants G0B4620N, G026325N, G026225N), KU Leuven (C1 grant C14/24/122 and C3 grant C3/23/067), VLIR-UOS (iBOF grant, iBOF/21/048, for ‘MIMICRY’ consortium), Olivia Hendrickx Research Foundation (OHRF) and a European Union (EU) Mission Cancer grant for the GLIOMATCH consortium (project no. 101136670). L.G. is or has been supported (as a PI unless otherwise indicated) by one R01 grant from the NIH/NCI (CA271915), by two Breakthrough Level 2 grants from the US DoD BCRP (BC180476P1, BC210945), by a Transformative Breast Cancer Consortium grant from the US DoD BCRP (W81XWH2120034, PI: Formenti), by a U54 grant from NIH/NCI (CA274291, PIs: Deasy, Formenti, Weichselbaum).
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Authors and Affiliations
Cancer Signalling and Microenvironment Program, Fox Chase Cancer Center, Philadelphia, PA, USA
Lorenzo Galluzzi
Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA
Kellie N. Smith
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
Kellie N. Smith
Department of Pathology, University of Cambridge, Cambridge, UK
Adrian Liston
Laboratory of Cell Stress & Immunity, Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium
Abhishek D. Garg
- Lorenzo Galluzzi
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- Kellie N. Smith
Search author on:PubMed Google Scholar
- Adrian Liston
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- Abhishek D. Garg
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A.D.G. conceived the article. A.D.G. and L.G. wrote the manuscript with critical input from A.L. and K.N.S. A.D.G. prepared the display items. All authors approved the submitted version of the article.
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Correspondence toLorenzo Galluzzi orAbhishek D. Garg.
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A.D.G. received consulting/advisory/lecture honoraria or R&D contracts from Boehringer Ingelheim (Germany), Miltenyi Biotec (Germany), Novigenix (Switzerland), Sotio (Czech Republic) and IsoPlexis (USA). L.G. holds or has held research contracts with Lytix Biopharma, Promontory and Onxeo, has received consulting or advisory honoraria from Boehringer Ingelheim, AstraZeneca, OmniSEQ, Onxeo, The Longevity Labs, Inzen, Imvax, Sotio, Promontory, Noxopharm, EduCom, AbbVie and the Luke Heller TECPR2 Foundation, and holds Promontory stock options. K.N.S. has received honoraria from Adaptive Biotechnologies and Illumina, Inc., has received research support from AbbVie, Bristol Myers Squibb and AstraZeneca, holds several patents related to the MANAFEST technology and TCR discovery, and is a scientific founder of Clasp Therapeutics. The other authors declare no competing interests.
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Galluzzi, L., Smith, K.N., Liston, A.et al. The diversity of CD8+ T cell dysfunction in cancer and viral infection.Nat Rev Immunol25, 662–679 (2025). https://doi.org/10.1038/s41577-025-01161-6
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