Mesothelin as Biomarker and Therapeutic Target for Immunotherapy in Cancer.

Cancer remains a critical global health concern due to late detection, drug resistance, and high mortality. Mesothelin (MSLN) is a glycoprotein highly expressed on the surface of various cancer cells, including those of ovarian, pancreatic, and gastric cancers. Thus, it could be a valuable target for both as a biomarker and for immunotherapy. This review summarizes MSLN biology in cancer, current immunotherapeutic strategies targeting MSLN, associated clinical challenges, and emerging avenues to enhance immunotherapy efficacy. During cancer progression, MSLN acts as a cellular accelerator, promoting cell division and survival. It activates several critical signaling pathways, including nuclear factor k-light-chain-enhancer of activated B cells (NF-κB), interleukin-6 and its soluble receptor (IL-6/sIL-6R), and c-Jun N-terminal kinase (JNK), thereby promoting epithelial-mesenchymal transition and angiogenesis. Various MSLN-targeting immunotherapies, including monoclonal antibodies, chimeric antigen receptor-T cells, cytokine therapies, and vaccines, have shown preclinical and early clinical efficacy. However, immune evasion, an immunosuppressive tumor microenvironment, antigen heterogeneity, tumor immune escape, and off-tumor toxicities continue to hinder the broad clinical success of these modalities. Nonetheless, rational combinations of MSLN-directed therapies with other immunomodulatory strategies, optimized patient stratification, and advances in vaccine and adoptive cell therapy design hold promise for overcoming resistance and improving patient outcomes.