TSPAN33 is a tetraspanin protein belonging to the TspanC8 subgroup that functions as a critical regulator of ADAM10 maturation, trafficking, and substrate specificity 1. As a component of the tetraspanin web, TSPAN33 directly interacts with ADAM10 to facilitate its exit from the endoplasmic reticulum and trafficking to the cell surface 1. TSPAN33 negatively regulates Notch signaling by modulating ADAM10-mediated Notch cleavage and enhances TLR-triggered macrophage activation through NOTCH signaling modulation 2. In B lymphocytes, TSPAN33 regulates endocytosis, adhesion, and migration by controlling plasma membrane tension and integrin expression 3. TSPAN33 is selectively expressed in activated B cells but absent in resting B cells, and is upregulated in several B cell lymphomas and autoimmune conditions including rheumatoid arthritis and systemic lupus erythematosus 4. In spermatogonial stem cells, TSPAN33 marks putative stem cell populations and is associated with TGF-β signaling-mediated self-renewal 5. Clinically, TSPAN33 serves as a biomarker for myocardial infarction, being significantly downregulated in exosomes from MI patients 6, and represents a potential therapeutic target for B cell malignancies and autoimmune diseases through selective depletion strategies 7.