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<p>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 <i>NF2</i> 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.</p>

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Merlin deficiency supports an immunosuppressive milieu in breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月9日

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  • Mohamed H. Elbahoty,
  • Brandon J. Metge,
  • Amr R. Elhamamsy,
  • Ian Miranda,
  • Melanie Aldridge,
  • Bohan Ning,
  • Hua Guo,
  • Dongquan Chen,
  • Lalita A. Shevde

摘要

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.