β2-microglobulin (β2M) functions as a chaperon to maintain structural stability of MHC class I complex that is associated with antigen presentation to cytotoxic (CD8+) T lymphocytes. Cancerous cells in β2M loss-of-function are thought to avoid immune surveillance. As increased level of β2M present in tissue/serum is significantly associated with tumor status in various cancers, β2M may become an important prognostic and survival factor in a range of malignancies. It is believed that β2M acts as hormone-like molecule to trigger a pleiotropic signaling via a ligand-to-receptor binding mechanism. Anti- β2M monoclonal antibodies successfully induce apoptosis in malignant cells, suggesting a surprising therapeutic approach. Of note, β2M is largely localized in the cytoplasm of advanced oral cavity squamous cell carcinoma (OCSCC), in contrast to that in the plasma membrane of normal oral mucosa. This suggests that β2M-derived intracellular signaling might be preceded by its accumulation in the cytoplasm of epithelial cells of tumors. Hence, translocation of β2M from cell surface to cytoplasm in advanced tumors may shed light on the mechanism of β2M-mediated tumorigenesis.