We are interested how cancer stem cells can execute these programs to favor immune-evasion and immunotherapy resistance. We have found that LCOR, a mammary epithelial differentiation factor, directly binds to the MHC and antigen presentation machinery (APM) genomic cluster in chromosome 6 and orchestrate APM expression in differentiated cells. We describe how normal mammary stem cells and cancer stem cells downregulate LCOR shutting down MHC/APM gene expression, which leads to acquired immunotherapy resistance in breast cancer preclinical models, alongside clinical validations. In order to avoid immunoediting and the emergence of immunotherapy resistance phenotypes, we have developed an innovative LCOR mRNA therapy to modulate the cell fate differentiation of CSCs reducing tumor phenotypic heterogeneity in vitro and in vivo. Systemic administration of nanobodies with LCOR mRNA induces CSC differentiation and re-expression of APM, thus preventing immune-evasion and driving complete immunotherapy response in experimental metastasis preclinical models. Moreover, in metastasis immunoediting assays using single-cell transcriptomic, we have observed how the metastatic colonization is dependent on immune-evasive CSC phenotypes upon arrival at distant organs. Therefore, innovative mRNA therapies in combination with immunotherapy represent novel therapeutic opportunities for caner metastasis.