Mucin 1 (MUC1) in the Diagnosis, Treatment and Translational Application of Malignant Tumors

Mucins belong to a family of high-molecular-weight (>200 kD) glycoproteins, with 9 members identified to date. Their molecular structure consists of a peptide core and glycans, where glycans account for 50%-90% of the weight and are mostly linked to the peptide core via O-glycosidic bonds. As a typical type I transmembrane protein, MUC1 mucin is primarily expressed on the luminal or glandular surface of epithelial cells in various tissues and organs under physiological conditions, presenting an apical polar distribution. Recent studies have found that MUC1 is also expressed in multiple hematopoietic cells, including T cells, B cells, and dendritic cells.

During tumorigenesis and progression, MUC1 exhibits characteristic abnormal expression patterns, specifically: ① significantly upregulated expression, reaching more than 100-fold that of normal tissues; ② loss of polar distribution on the cell surface, transforming from apical-specific to diffuse expression across the entire cell surface; ③ structural alterations, mainly due to abnormal glycosylation, exposing new glycan structures and peptide epitopes. Notably, the MUC1 isoform MUC1/Y shows tumor-specific expression, highly expressed in breast and ovarian cancer tissues but negative in adjacent normal tissues.

Based on the abnormal expression characteristics of MUC1 in tumor tissues, it has become a potential tumor biological marker, currently applied in tumor diagnosis and biological therapy. In recent years, significant progress has been made in studying the immunobiological functions of MUC1, providing a key theoretical basis for exploring new entry points for tumor biological therapy.

As a highly glycosylated type I transmembrane protein on the surface of epithelial cells, MUC1 plays a critical role in the development of malignant tumors and immune escape. The MUC1 gene localizes to human chromosome 1q22, encoding a polypeptide backbone of 1,255 amino acids, with structural features including three main functional domains: an extracellular region composed of 20-amino-acid tandem repeat (TR) sequences, each containing 5 potential O-glycosylation sites; a hydrophobic α-helical transmembrane region; and a 72-amino-acid intracellular tail with multiple phosphorylation sites and protein interaction motifs. Under normal physiological conditions, MUC1 is mainly expressed on the apical membrane surface of glandular epithelial cells, protecting epithelial tissues by forming a physical barrier. However, in more than 90% of epithelial-derived malignant tumors (including breast, pancreatic, lung, ovarian, and colorectal cancers), MUC1 shows abnormal overexpression and altered glycosylation modification, with loss of polar distribution and a full-membrane expression pattern. Such tumor-specific expression characteristics make MUC1 a highly promising diagnostic marker and therapeutic target.

In-depth studies on molecular mechanisms have revealed that the carcinogenic effects of MUC1 are achieved through multi-pathway collaboration. First, the intracellular domain of MUC1 (MUC1-CT) directly interacts with key signaling molecules such as β-catenin, p53, and NF-κB, regulating important signaling pathways like Wnt, p53, and NF-κB. For example, phosphorylation modification of MUC1-CT stabilizes β-catenin and promotes its nuclear translocation, activating downstream proliferation-promoting genes such as cyclin D1 and c-myc. Second, abnormal glycosylation of tumor-associated MUC1 (tMUC1) (e.g., expression of Tn, sialyl-Tn, and TF antigens) exposes new peptide and glycan epitopes, which can be recognized by the immune system. Additionally, MUC1 promotes tumor malignancy through the following mechanisms: interacting with adhesion molecules like ICAM-1 to facilitate metastasis; regulating HIF-1α expression to enhance tumor hypoxia adaptation; activating the PI3K/AKT/mTOR pathway to promote cell survival; and inhibiting T cell activation and NK cell killing function to mediate immune escape. Notably, MUC1 can also remotely regulate the tumor microenvironment through exosomes, influencing stromal cell activation and angiogenesis.

In the field of clinical application, translational research on MUC1 mainly focuses on three directions: molecular diagnosis, targeted therapy, and prognostic evaluation. In terms of diagnosis, liquid biopsy technologies based on MUC1 have developed rapidly, including detection of MUC1 fragments in serum (such as CA15-3, CA27.29) and MUC1 expression in circulating tumor cells. Among them, CA15-3, as the first FDA-approved breast cancer biomarker, is of great value in efficacy monitoring and recurrence warning. Targeted therapy strategies mainly include: immunotoxins (such as MUC1-PE38), antibody-drug conjugates (such as SAR566658), CAR-T cell therapy (targeting MUC1 tumor-associated antigens or tumor-specific antigens), dendritic cell vaccines (such as Tecemotide), and glycopeptide vaccines (such as PANVAC-VF). Particularly, vaccines designed against the variable tandem repeat sequences of MUC1 have shown good immunogenicity in pancreatic cancer clinical trials. Furthermore, MUC1 expression levels are closely related to tumor drug resistance, and its regulated autophagy process represents a new target for overcoming chemotherapy resistance.

Currently, the main scientific challenges in MUC1-targeted therapy include: antigen loss caused by tumor heterogeneity; complexity and individual differences in glycosylation modification; and regulatory barriers in the immunosuppressive microenvironment. Aiming at these bottlenecks, the new-generation therapeutic strategies focus on the following breakthroughs: developing multi-epitope combined targeting regimens (such as MUC1 and PD-L1 bispecific antibodies); designing glycosylation-specific CAR-T cells; using nanocarriers for co-delivery of MUC1 siRNA and chemotherapeutic drugs; and combining epigenetic regulators to enhance MUC1 antigen presentation. Recent studies have also found that MUC1 plays a key role in tumor stem cell maintenance, providing new ideas for developing radical therapies. Epigenetic analysis shows that the methylation status of the MUC1 promoter region can predict its sensitivity to demethylating drugs.

Future research directions should focus on: decoding the precise regulatory network of MUC1 glycosylation modification; developing precision treatment strategies based on MUC1 molecular typing; and optimizing multimodal combination therapy regimens. With the development of glycoproteomics, single-cell sequencing, and artificial intelligence technologies, MUC1 research is deepening from a single marker to the systems biology level. Especially in the field of tumor vaccines, personalized vaccine design based on MUC1 neoantigens, combined with immune checkpoint blockade therapy, is expected to break through the current bottleneck of solid tumor immunotherapy. In addition, the role of MUC1 in tumor microenvironment remodeling and metabolic reprogramming has received increasing attention, and breakthroughs in these basic research areas will provide new theoretical foundations and therapeutic targets for clinical translation.

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