Single-cell transcriptomics reveals TGF-β1–associated mesothelial-to-mesenchymal transition promoting tumor progression and immune suppression in mesothelioma

Malignant mesothelioma (MESO) is a rare and highly aggressive malignancy characterized by substantial heterogeneity, early dissemination, and limited therapeutic options. Despite advances in multimodal therapy, prognosis remains dismal, underscoring the need for mechanistic insights to guide new treatments. Here, we integrated single-cell RNA sequencing of primary and metastatic MESO lesions and malignant effusions with independent patient-derived single-cell datasets, enabling comprehensive characterization of tumor and microenvironmental cell populations. We identified a reproducible fibroblast-like malignant mesothelial cell state across independent cohorts, histological phenotypes, and anatomical sites. The emergence of this cell state was associated with TGF-β1-induced mesothelial-to-mesenchymal transition (MMT) and was linked to enhanced malignant behavior, metastatic progression, adverse clinical outcomes, and immunosuppressive microenvironmental features. IGFBP3 was enriched in fibroblast-like malignant cells, and conditioned-medium experiments showed that IGFBP3 neutralization partially reduced immune-cell apoptosis, supporting its role as a candidate mediator of immune modulation. To further assess the therapeutic relevance of this TGF-β1-associated cell state, we pharmacologically blocked TGF-β signaling in patient-derived tumor-like clusters, which increased IFN-γ and GZMB expression, consistent with enhanced immune cytotoxicity. Together, these findings highlight the TGF-β1-associated fibroblast-like malignant program as potential therapeutic vulnerabilities in MESO.