REVIEW article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Unlocking the Mystery of the PD-1/PD-L1 axis: beyond the checkpoint hype
Provisionally accepted
- 1Institut de Duve, Brussels, Belgium
- 2Ludwig Institute for Cancer Research Brussels Branch of Human Cancer Cell Genetics, Brussels, Belgium
- 3CHU Helora asbl, Mons, Belgium
- 4WELBIO asbl, Wavre, Belgium
- 5University of Oxford Nuffield Department of Medicine, Oxford, United Kingdom
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The discovery of the PD-1 receptor and its ligand PD-L1 revolutionized our understanding of immune regulation and, with CTLA-4, provided the conceptual foundation for immune checkpoint blockade, now a cornerstone of cancer therapy. Early models emphasized a simplistic view in which PD-L1 expression by tumor cells directly inhibited cytotoxic T lymphocytes through PD-1 engagement. However, recent findings reveal that this pathway is far more complex, involving multilayered regulation of PD-L1 expression, extensive post-translational modifications, and a broad spectrum of interacting partners. In addition to tumor cells, multiple immune and stromal populations, including dendritic cells, macrophages, T cells, and endothelial cells, express PD-L1 and critically shape antitumor immunity and therapeutic responses. Moreover, PD-L1 exerts intrinsic, non-immune functions within tumor cells, including regulation of proliferation, apoptosis resistance, and metabolic adaptation. PD-1 itself, long viewed as a T-cell-restricted inhibitory receptor, is now recognized as functionally relevant on additional cell types such as natural killer cells, myeloid cells, and even tumor cells, further diversifying its role in immune regulation and tumor biology. Together, these insights challenge the classical dogma and call for a refined view of the PD-1/PD-L1 axis that accounts for its cellular heterogeneity, molecular complexity, and bidirectional signalling. Incorporating this knowledge into clinical practice will be essential to improve patient stratification, overcome therapeutic resistance, and design innovative combination strategies to fully exploit the potential of immune checkpoint blockade.
Keywords: PD-1/PD-L1, T cell biology, Immune Regulation, Tumor Microenvironment, immuneevasion, Signal Transduction, post-translational regulation, protein-protein interactions
Received: 19 Sep 2025; Accepted: 13 Nov 2025.
Copyright: © 2025 Desimpel, Petit, Van den Eynde and Zhu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jingjing Zhu, jingjng.zhu@uclouvain.be
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