PD-1/PD-L1 signaling in neurological and psychiatric disorders: neuroimmune mechanisms and therapeutic potential

Programmed cell death protein-1 (PD-1) and its ligand PD-L1 constitute a central immune checkpoint pathway that maintains immune tolerance and limits excessive inflammation. Beyond oncology, emerging evidence indicates that PD-1/PD-L1 signaling plays fundamental roles in central and peripheral nervous system (CNS and PNS) homeostasis. In the brain, PD-1/PD- L1 restrains neuroinflammation, regulates microglial and astrocytic activation, and influences synaptic function and neurodevelopment, thereby contributing to the pathophysiology of autoimmune demyelinating disease, stroke, Alzheimer's disease, Parkinson's disease, and psychiatric disorders. Outside the brain, PD-1/PD-L1 signaling modulates nociceptive processing in sensory ganglia and the spinal cord, as well as the trafficking and function of circulating monocytes, revealing a multi-layered neuroimmune regulatory network. However, the functional impacts of PD-1/PD-L1 are highly dependent on factors like disease context, cell type, disease stage, and sex. Accordingly, we critically evaluate the therapeutic opportunities and limitations of both PD-1/PD-L1 blockade and agonism across these diverse neurological and psychiatric conditions. Due to major translational hurdles, including limited CNS drug penetration, immune-related adverse events, and the opposing outcomes of pathway modulation in different compartments or phases of disease, future strategies will likely require spatiotemporally controlled and cell-specific modulation of PD-1/PD-L1 signaling, improved central nervous system drug delivery, and biomarker-guided patient stratification. Collectively, this review integrates CNS, PNS, and systemic immune interactions to position PD-1/PD-L1 as a potential target for next-generation neuro-immunotherapies across neurological and psychiatric disorders.