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

[UNLABELLED] 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 MHC-I expression on the surface of tumor cells, which is required for the recognition of tumor-specific antigens by CD8+ T cells. In samples from patients with breast cancer, TSPAN13 expression negatively correlated with CD8+ T-cell infiltration. Mechanistically, TSPAN13 enhanced the ubiquitination of MHC-I by recruiting STIP1 homology and U-box containing protein 1, thereby promoting lysosomal degradation and significantly reducing MHC-I levels on the cell surface. Both in vitro and in vivo experiments demonstrated that the 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.

[SIGNIFICANCE] TSPAN13 decreases MHC-I surface expression and CD8+ T-cell activation to induce an immunosuppressive state in breast cancer, supporting targeting TSPAN13 as an immunotherapeutic strategy.