PDCD1LG2 (PD-L2) is a ligand for the inhibitory receptor PD-1 that plays a critical role in immune tolerance by suppressing T cell activation 1. Engagement of PD-1 by PD-L2 dramatically inhibits T cell receptor-mediated proliferation and cytokine production through cell cycle arrest in G0/G1 phase, with effects varying based on antigen concentration 1. PD-L2 expression is induced by interferon signaling, with interferon-gamma and interferon-beta activating the JAK1/JAK2-STAT1/STAT2/STAT3-IRF1 axis to regulate PD-L2 promoter activity 2. Post-translational N-glycosylation of PD-L2, catalyzed by fucosyltransferase 8 downstream of STAT3, stabilizes the protein and enhances its immunosuppressive function by promoting PD-1 binding 3. In cancer contexts, PD-L2 expression correlates with immune evasion and poor prognosis across multiple tumor types, associating with immune cell infiltration and immunosuppressive biomarkers 4. Additionally, cancer-associated fibroblasts produce PD-L2 in response to interferon-gamma, promoting regulatory T cell accumulation through the PD-L2-RGMB axis 5. Therapeutically, PD-L2 is targetable with monoclonal antibodies like pembrolizumab, and STAT3 or PD-L2 glycosylation inhibition may enhance immunotherapy efficacy 3. These findings establish PD-L2 as a central immune checkpoint regulating T cell tolerance with significant implications for cancer immunotherapy and autoimmune disease.