Innovative approaches and challenges of MUC1 as a therapeutic target in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a type of breast cancer that lacks the estrogen, progesterone, and HER2 receptors, and is more aggressive with a poor prognosis, and is associated with a high incidence of early distant recurrence within the first 3-5 years after diagnosis. MUC1 is a transmembrane mucin that is highly expressed and altered in glycosylation on TNBC cells and it leads to tumor progression and chemoresistance via its dysregulated signaling pathways, making it a potential therapeutic target and biomarker. The structure of MUC1, its physiological function and pathological role in TNBC is summarized in this review. We also review the different therapeutic modalities targeting MUC1, such as MUC1-specific aptamers, targeting with nanoparticles, peptide and small molecule inhibitors of MUC1-C and emerging biologics like antibody-drug conjugates and CAR-T-cell therapies and their preclinical effectiveness and early translation into TNBC. The challenges to overcome, such as issues with targeting specificity, tumor heterogeneity, antigen shedding, lack of good preclinical models, and other translational obstacles, are critically examined, as is the regulatory landscape of MUC1-targeted nanotherapeutics, including key FDA/EMA considerations for bringing MUC1-directed aptamer and nanoparticle platforms into clinical use, and biomarker-guided patient selection. This article summarizes the potential of MUC1 targeted strategies for better management of TNBC and the future directions to further enhance therapeutic efficacy, including rational combination therapy and multimodal imaging, while minimizing off-target effects, leveraging the integration of insights from gene expression profiling (TNBC-BLBC overlap), receptor biology (e.g. integrins, ICAM 1), and advances in nanomedicine and immuno oncology.