Molecular alterations of muc1 and their therapeutic exploitation: Emerging opportunities in cancer therapy

Mucin 1 (MUC1), a transmembrane glycoprotein (TGP) normally expressed on epithelial surfaces, is aberrantly overexpressed and hypoglycosylated (HG) in a wide spectrum of malignancies, including lung, breast, pancreatic, ovarian, and hematological cancers. These structural and biochemical alterations drive oncogenesis by activating signaling pathways such as NF-κB, PI3K/AKT and Wnt/β-catenin, while also fostering immune microenvironmental variability (IMV) and therapeutic resistance. Over the past decades, MUC1 has emerged as a versatile biomarker and therapeutic target, prompting extensive investigation into MUC1-directed strategies. Clinical approaches have encompassed vaccines, monoclonal and bispecific antibodies (ABs), antibody drug conjugates (ADC), CAR-T cell therapy and radiopharmaceuticals. Despite promising preclinical results, early-generation vaccines and ABs have shown limited efficacy in clinical trials (CT), largely due to tumor heterogeneity (TH), diverse glycosylation (GSY) patterns, and the immunosuppressive (IMS) tumor microenvironment (TME). Ongoing research is refining antigen selection, optimizing tumor stratification, and integrating combination strategies to enhance therapeutic responses. The presented review highlights the molecular underpinnings of MUC1 in cancer biology, while critically evaluating the successes and limitations of current MUC1-targeted therapies. Beyond its pivotal role in tumor progression (TP) and therapeutic resistance, MUC1 remains a compelling focus for innovative interventions. Emerging strategies including bispecific ABs, ADC, radiopharmaceuticals, and CAR-T cells are redefining the therapeutic landscape. With advancing precision in antigen design, patient stratification, and combination strategies, MUC1 is poised to transition from a promising biomarker to a cornerstone of next-generation cancer therapeutics.