IGLL5 (immunoglobulin lambda-like polypeptide 5) is a B cell-associated protein with roles in immune regulation and hematologic malignancies. Functionally, IGLL5 acts as a ligand for lymphotoxin beta receptor (LTβR) on high endothelial venules; IGLL5-LTβR binding induces conformational changes in LTβR that inhibit non-canonical NF-κB signaling 1. In cancer immunology, IGLL5+ B cell subsets disrupt tertiary lymphoid structures (TLSs) that normally promote anti-tumor immunity, and blocking IGLL5 preserves TLSs and enhances immunotherapy efficacy in bladder cancer and pan-cancer models 1. IGLL5 expression correlates with tumor-infiltrating immune cells in clear cell renal cell carcinoma 2. Clinically, IGLL5 mutations are emerging as significant drivers of hematologic malignancies. IGLL5 is under positive selection in clonal hematopoiesis and correlates with increased infection, mortality, and hematological malignancy risk 3. In chr22 lymphocytic leukemia, IGLL5 mutations occur in 29.3% of Taiwanese patients and co-occur with MYD88 mutations, predicting poor prognosis 4. IGLL5 mutations are also recurrent in post-transplant lymphoproliferative disorder (29%), multiple myeloma, and follicular lymphoma 5, 6, 7. These findings suggest IGLL5 functions as both an immune checkpoint regulator and a disease driver, making it a promising therapeutic target.