Tetraspanin 13 Enhances Immune Evasion in Breast Cancer by Promoting MHC-I Degradation

Abstract In contrast to highly immunogenic malignancies, breast cancer frequently features a "cold" tumor immune microenvironment marked by low immune cell infiltration and limited activation of effector T cells. This immunosuppressive phenotype poses a substantial barrier to the efficacy of immune checkpoint inhibitors and other immunotherapeutic approaches, highlighting the need to identify mechanisms limiting antitumor immunity. In this study, we identified a role for tetraspanin 13 (TSPAN13) in regulating major histocompatibility complex class I (MHC-I) expression on the surface of tumor cells, which is required for the recognition of tumor-specific antigens by CD8+ T cells. In breast cancer patient samples, TSPAN13 expression negatively correlated with CD8⁺ T cell infiltration. Mechanistically, TSPAN13 enhanced the ubiquitination of MHC-I by recruiting STUB1, thereby promoting lysosomal degradation and significantly reducing MHC-I levels on the cell surface. Both in vitro and in vivo experiments demonstrated that loss of TSPAN13 in tumor cells significantly enhanced CD8+ T cell activity and improved cytotoxicity against tumor cells. Moreover, suppression of TSPAN13 expression significantly increased tumor sensitivity to anti-PD-L1 therapy. Together, these findings suggest that TSPAN13 is a potential therapeutic target for breast cancer immunotherapy.