ULBP2 (UL16 binding protein 2) is a surface-expressed ligand that binds and activates the NKG2D receptor on natural killer cells, mediating NK cell-dependent cytotoxicity 1. However, ULBP2 has emerged as a paradoxical immune regulator in cancer: tumor-expressed surface ULBP2 suppresses NKG2D-mediated anti-tumor immunity through sustained exposure that reduces NKG2D expression and NK cell cytotoxic activity 1. In gastric cancer, ULBP2 overexpression activates TGF-β signaling to promote cancer-associated fibroblast activation and tumor progression 2. ULBP2 upregulation is associated with poor prognosis across multiple malignancies including cervical, colon, and breast cancers 3, 4, 5. METTL3-mediated m6A methylation regulates ULBP2 expression and affects cervical cancer radioresistance 3. Therapeutically, ULBP2-targeted CAR-T cells effectively eliminate gastric cancer cells in preclinical models and enhance immunotherapy efficacy 2, while ULBP2-targeted trispecific T cell engagers with integrated CD2 costimulation demonstrate superior tumor-killing efficacy 6. Interestingly, a non-linear association between ULBP2 and venous thromboembolism was identified through proteome-wide association studies 7.