Novel perspectives on MSLN-targeted cancer therapy: from molecular mechanisms to clinical translation

Mesothelin (MSLN) is a glycosylphosphatidylinositol (GPI)-anchored membrane protein that promotes malignant behaviors including tumor cell proliferation, migration and immune evasion through activation of multiple signaling pathways, such as MAPK/ERK and PI3K/AKT. MSLN is widely overexpressed in malignant tumors but shows low expression levels in normal tissues. This differential expression pattern renders MSLN an important clinical therapeutic target. Currently, MSLN-based tumor-targeting approaches predominantly involve antibody-drug conjugates (ADC), cancer vaccines, oncolytic viruses and chimeric antigen receptor T-cell (CAR-T) therapies. These therapeutic modalities have demonstrated encouraging efficacy in preclinical studies and phase I/II clinical trials. However, challenges such as unclear molecular mechanisms of MSLN signaling pathways and extracellular domain shedding impose limitations on targeted therapeutic strategies. Therefore, this review comprehensively discusses the gene and protein structures of MSLN, its biological functions, and related targeted therapeutic strategies, providing new insights into MSLN-targeted cancer therapy.