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Annual Review of Immunology

Volume 43, 2025

Molecular Mechanisms Governing CD8 T Cell Differentiation and Checkpoint Inhibitor Response in Cancer

  • Lisa Rausch1 and Axel Kallies1
  • Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia; email: [email protected]
  • Vol. 43:515-543 (Volume publication date April 2025)
  • Copyright © 2025 by the author(s).
    This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See credit lines of images or other third-party material in this article for license information.

Abstract

CD8 T cells play a critical role in antitumor immunity. However, over time, they often become dysfunctional or exhausted and ultimately fail to control tumor growth. To effectively harness CD8 T cells for cancer immunotherapy, a detailed understanding of the mechanisms that govern their differentiation and function is crucial. This review summarizes our current knowledge of the molecular pathways that regulate CD8 T cell heterogeneity and function in chronic infection and cancer and outlines how T cells respond to therapeutic checkpoint blockade. We explore how T cell–intrinsic and –extrinsic factors influence CD8 T cell differentiation, fate choices, and functional states and ultimately dictate their response to therapy. Identifying cells that orchestrate long-term antitumor immunity and understanding the mechanisms that govern their development and persistence are critical steps toward improving cancer immunotherapy.

Keyword(s): chronic infection, epigenetic regulators, exhausted CD8 T cells, PD-1, tissue-resident memory T cells, transcription factors
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2025-04-25
2025-06-19
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Molecular Mechanisms Governing CD8 T Cell Differentiation and Checkpoint Inhibitor Response in Cancer
Annual Review of Immunology 43, 515 (2025); https://doi.org/10.1146/annurev-immunol-082223-044122
/content/journals/10.1146/annurev-immunol-082223-044122
/content/journals/10.1146/annurev-immunol-082223-044122
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