Human mesothelin gene encodes a 71 kDa precursor protein, processed into a 31 kDa shed form (megakaryocyte potentiation factor, MPF) and a 40 kDa membrane protein MSLN anchored by glycosylphosphatidylinositol (GPI). MSLN can also generate truncated soluble forms (soluble mesothelin-related peptide, SMRP) through selective splicing or TNF-α convertase cleavage.
In most cancers, MSLN is uniformly expressed on cell surfaces with low cytoplasmic expression. Particularly, it is highly overexpressed in mesothelioma, epithelial ovarian cancer, and pancreatic cancer. Aberrant MSLN expression promotes cancer cell proliferation, local infiltration, metastasis, and resistance to cytotoxic agent-induced apoptosis, driving malignant transformation and invasiveness of tumors. It directly activates intracellular pathways through its GPI domain or interacts bidirectionally with its receptor CA125/MUC16, constituting activation of NF-κB, PI3K, and MAPK pathways to enhance proliferation and resistance to apoptosis.
In the past three years, most newly registered clinical trials targeting MSLN have been related to chimeric antigen receptor T cell therapy. Cell therapy has emerged as an effective strategy for treating solid tumors expressing MSLN, with safety, efficacy, and maximum tolerated doses of over a dozen CAR-T and CAR-NK cell therapies targeting MSLN currently being evaluated in phase 1/2 clinical trials.
