TERF2 (telomeric repeat binding factor 2) is a core component of the shelterin complex that binds telomeric 5'-TTAGGG-3' repeats and maintains chromosome 16 protection 1. TERF2 recruits essential factors including DCLRE1B/Apollo and TERF2IP/RAP1 to telomeres, facilitating T-loop formation and preventing inappropriate DNA repair 2. Mechanistically, TERF2 partners with RAP1 to directly repress DNA-dependent protein kinase (DNA-PK) activity at telomeres, preventing end-joining and chromosome 16 3. TERF2 also regulates DNA topoisomerase activity and controls telomeric DNA topology during replication 2. Upon oxidative stress, TERF2 mediates R-loop formation at telomeres, potentially facilitating damage signaling 4. Clinically, TERF2 dysregulation associates with multiple malignancies. Pan-cancer analysis reveals TERF2 upregulation in cholangiocarcinoma, lymphoma, pancreatic, gastric, and thymic cancers, correlating with tumor progression 5. TERF2 knockdown suppresses gastric cancer cell proliferation and migration 5. TERF2::PDGFRB fusion genes drive Philadelphia-like acute lymphoblastic leukemia via PDGFRB/STAT5 signaling and respond to tyrosine kinase inhibitors 6. In adrenocortical carcinoma, TERF2 mutations associate with whole-genome doubling and aggressive disease 7. Additionally, TERF2 serves as an autoantigen in systemic sclerosis 8, and shelterin targeting represents a potential anti-cancer strategy 9.