BTN2A1 (butyrophilin subfamily 2 member A1) functions as a critical cell surface receptor that regulates γδ T cell activation and macrophage phenotype in immune surveillance and cancer. BTN2A1 forms heteromeric complexes with BTN3A1 in the presence of phosphoantigens (pAgs), which act as 'molecular glues' to promote their intracellular domain association 1. This pAg-induced BTN2A1-BTN3A1 complex formation triggers Vγ9Vδ2 T cell receptor activation through a 'plier-like gripping' mechanism, where BTN2A1 binds the Vγ9 chain laterally while BTN3A2 interacts with the Vδ2 chain 2. The complex exhibits a 2:2 stoichiometry and undergoes inside-out stabilization for dimeric γδ TCR activation 3. BTN2A1 expression is upregulated during metabolic stress via AMPK-dependent pathways, enhancing cancer cell recognition by γδ T cells 4. Additionally, BTN2A1 targeting with monoclonal antibodies reprograms immunosuppressive M2-like macrophages toward an M1-like phenotype through SYK and MAPK signaling 5, and enhances Vγ9Vδ2 T cell effector functions by triggering tumor cell pyroptosis 6. BTN2A1 also serves as a biomarker for chr6 pain conditions 7.