Merlin deficiency supports an immunosuppressive milieu in breast cancer.

Despite substantial advances in early detection and therapeutic strategies, breast cancer remains a major cause of cancer-related morbidity and mortality worldwide. Changes in cytoskeletal proteins that typically regulate cellular architecture underpin tumor progression. Merlin, encoded by the NF2 gene and a member of the ezrin-radixin-moesin protein family, functions as a critical cytoskeletal linker protein and a tumor suppressor that governs multiple oncogenic pathways and restricts epithelial-mesenchymal plasticity. While Merlin deficiency alters cellular architecture, the precise impact of a Merlin-deficient breast tumor on remodeling its immune microenvironment remains largely undefined. In this study, we demonstrate that in breast cancer, Merlin deficiency displays attributes consistent with enhanced epithelial-mesenchymal plasticity and enrichment of Hedgehog signaling. In vivo, Merlin-deficient tumors displayed accelerated growth and an immunosuppressive milieu characterized by increased abundance of regulatory T cells and M2-like macrophages. Treatment with Vismodegib, a pharmacological Hedgehog pathway inhibitor, reduced tumor growth of Merlin-deficient basal-like tumors, accompanied by a decrease in tumor-infiltrating regulatory T cells and immunosuppressive M2-like macrophages, and increased recruitment of pro-inflammatory M1-like macrophages. The data present Hedgehog inhibition as a targetable vulnerability of Merlin-deficient basal-like, triple-negative breast cancer.