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Understanding the Therapeutic Potential of PD-1 Agonism in Inflammatory and Autoimmune Disorders

BioDrugs (2026)

The therapeutic potential of programmed cell death-1 (PD-1) agonism is increasingly recognized as a cornerstone for restoring immune tolerance in autoimmune diseases. However, while PD-1 antagonism has revolutionized oncology, a critical knowledge gap remains regarding optimal strategies to therapeutically harness PD-1 activation. This review provides a comprehensive analysis of the mechanical and molecular requirements for inducing PD-1 signaling, addressing the current lack of a unified framework for agonistic drug development. We first delineate the fundamental biology of PD-1 signaling in maintaining peripheral tolerance. We then evaluate four primary mechanistic strategies currently under investigation: (1) receptor dimerization and clustering; (2) membrane-proximal epitope binding; (3) modulation of antibody binding affinity; and (4) Fcγ-receptor crosslinking.

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