TMIGD2 is a transmembrane immunoglobulin-domain receptor that functions as a costimulatory molecule in immune regulation and cell-cell interactions. As a T and NK cell costimulator, TMIGD2 interacts with HHLA2 to enhance T-cell proliferation and cytokine production through AKT-dependent signaling 1. In normal physiology, TMIGD2 is constitutively expressed on naive T cells and NK cells 2, where it promotes positive regulation of angiogenesis and cell migration. In disease contexts, TMIGD2 becomes pathologically relevant in acute myeloid leukemia (AML), where it is aberrantly expressed on leukemia stem cells (LSCs) and drives proliferation via ERK1/2-p90RSK-CREB signaling while blocking myeloid differentiation 3. Importantly, TMIGD2 is required for LSC self-renewal but dispensable for normal hematopoiesis, making it an attractive therapeutic target. Anti-TMIGD2 monoclonal antibodies effectively reduce leukemia burden in patient-derived xenografts 3. Clinically, TMIGD2 shows therapeutic promise in solid tumors as a costimulatory domain in chimeric antigen receptor (CAR) T-cell constructs targeting B7-H3. TOP CAR-T cells incorporating TMIGD2 costimulation demonstrate superior antitumor activity with reduced exhaustion and enhanced persistence compared to CD28/4-1BB constructs 4. In glioma, high TMIGD2 expression correlates with favorable prognosis and immune cell infiltration, identifying it as a potential agonistic immunotherapy target 2.