MUC1 in cancer

Abstract Mucin 1 (MUC1), a prototypical transmembrane mucin, is aberrantly overexpressed and hypoglycosylated in a broad spectrum of epithelial malignancies and hematologic cancers, with its expression level closely correlated with tumor proliferation, metastatic invasion, therapeutic resistance, and poor patient prognosis. This review aims to systematically delineate the structural characteristics and biological functions of MUC1, with a particular focus on the regulatory mechanisms and pathogenic roles of its C-terminal subunit (MUC1-C), and to comprehensively summarize the latest advances in MUC1-targeted anti-tumor therapeutic strategies. We performed an integrated and in-depth synthesis of existing peer-reviewed literature regarding the molecular basis of MUC1 in tumorigenesis, its involvement in oncogenic signaling cascades, and the development of therapeutic modalities targeting this molecule. Upon autoproteolysis, MUC1 is cleaved into two non-covalently linked subunits: the extracellular N-terminal subunit (MUC1-N) that mediates mucosal barrier protection, and the transmembrane MUC1-C, which acts as a central signaling hub to modulate multiple core oncogenic pathways including EGFR, PI3K/AKT/mTOR, NF-κB, and STAT3, thereby inhibiting apoptosis, driving malignant proliferation, epigenetic reprogramming, immune evasion, and inflammation-related pathogenesis. To date, multiple MUC1-targeted therapies, including monoclonal antibodies, antibody–drug conjugates, small molecule inhibitors, CAR-T/NK cell therapies, and cancer vaccines, have advanced to clinical trials, while emerging approaches such as RNA interference, oncolytic virus therapy, and combination immunotherapies have yielded promising anti-tumor efficacy in preclinical in vitro and in vivo studies. Collectively, MUC1, especially the MUC1-C subunit, represents a pivotal and promising target for cancer therapy. Both ongoing clinical investigations and novel MUC1-targeted therapeutic modalities exhibit substantial translational potential, though further in-depth mechanistic research and rigorous clinical validation are still required to optimize their therapeutic efficacy and safety.