Immune MAL2-practice: breast cancer immunoevasion via MHC class I degradation

The success of tumor immunotherapy, while partial, confirms the existence and importance of tumor immunosurveillance. CD8+ T cell recognition of tumor-specific peptides bound to MHC class I (MHC-I) molecules is central to this process. In this issue of the JCI, Fang, Wang, et al. describe a unique tumor immunoevasion strategy based on endocytosis and degradation of MHC-I complexes mediated by the trafficking factor MAL2. Notably, MAL2 expression was associated with poor prognosis of breast cancer, and its downregulation enhanced CD8+ T cell recognition of breast cancer in various experimental models. This work demonstrates that a deeper understanding of tumor interference with MHC-I stability and trafficking has considerable potential for enhancing immunotherapies.