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Mesothelin (MSLN) is among the most studied cancer-related antigens, and it is extensively studied as a therapeutic target for the treatment of various malignancies, including pleural mesothelioma, pancreatic ductal adenocarcinoma, and ovarian cancer. However, despite the development of many MSLN-targeting strategies, such as antibody-drug conjugates (ADC), bispecific antibodies, and CAR-T cells, clinical responses have remained limited, underscoring the need for a deeper understanding of MSLN biology. Over the past decades, many studies have highlighted a link between MSLN and cancer progression and its association with specific features within the tumor microenvironment (TME). More recently, mechanistic evidence has emerged showing the involvement of MSLN in the establishment of key malignant features, such as the epithelial-to-mesenchymal transition (EMT) and matrix metalloproteinase 7-mediated remodeling of the extracellular matrix (ECM). Furthermore, these studies also show a direct role for MSLN in the immunosuppressive polarization of the TME through the interaction with CD206 macrophage receptors (leading to an M2-like polarization) and by promoting the transition of mesothelial cells into specific cancer-associated fibroblasts (CAFs). This review synthesizes current evidence on MSLN transcriptional regulation and its functional implications in invasion, metastasis, and immune evasion. We also summarize ongoing therapeutic strategies targeting MSLN and discuss how TME-driven resistance mechanisms are shaping the next generation of MSLN-directed therapies. By integrating molecular insights with translational perspectives, this work provides a comprehensive overview of MSLN biology and its emerging therapeutic relevance in cancer.