While our previous work demonstrated that CD44 homophilic binding mediates tumor cell aggregation (Liu et al., 2019; Kawaguchi et al., 2020), in this study we propose that CD81 interacts with CD44 to promote intracellular CD44-CD81 heterodimer formation and possibly intercellular tetramer formation between two neighboring cells. The gene discussed is CD81; the disease is neoplasm.