Programmed cell death protein 1 (PD-1) signaling pathway (PD-1/PD-L1/PD-L2 pathway)

The Programmed cell death protein 1 (PD-1) signaling pathway is a critical immune checkpoint mechanism that maintains peripheral tolerance and prevents autoimmunity by downregulating T cell activity. PD-1 is expressed on the surface of activated T cells, B cells, and myeloid cells, and it interacts with two primary ligands: Programmed death-ligand 1 (PD-L1) and Programmed death-ligand 2 (PD-L2). In a healthy physiological state, this interaction limits the duration and intensity of immune responses to protect normal tissues from collateral damage. However, many tumors exploit this pathway by overexpressing PD-L1, which binds to PD-1 on tumor-infiltrating lymphocytes, leading to T cell exhaustion and immune evasion. Therapeutic intervention using immune checkpoint inhibitors (ICIs) targets this axis to disrupt the inhibitory signal, thereby reinvigorating the anti-tumor immune response. This pathway has become a cornerstone of modern oncology, with multiple approved drugs significantly improving survival across various malignancies, including melanoma, non-small cell lung cancer, and renal cell carcinoma (PubMed, 2023; UniProt, 2024).

Other names

PD-1/PD-L1 checkpointPDCD1 signalingCD279/CD274/CD273 axisB7-H1/B7-DC signalingImmune checkpoint pathway

Monoclonal antibodies bind to either the PD-1 receptor on T cells or the PD-L1 ligand on tumor/immune cells, preventing their interaction. This blockade restores the effector function of exhausted T cells, allowing the immune system to recognize and eliminate cancer cells (NIH, 2023; StatPearls, 2024).