MUC1 as an Emerging Target for Antibody–Drug Conjugates: Opportunities and Challenges in Precision Oncology

Antibody–drug conjugates (ADCs) are redefining cancer therapy by enabling targeted delivery of cytotoxic agents. While traditional ADCs have focused on well-validated targets like HER2 and EGFR, interest is growing in less-explored antigens such as MUC1. MUC1 is overexpressed and aberrantly glycosylated in multiple epithelial cancers, making it a promising yet technically challenging ADC target. This review discusses MUC1’s structure, oncogenic role, expression profile, and the current landscape of MUC1-targeted ADCs in development. Despite clinical hurdles, innovative approaches—such as bispecific ADCs, novel payloads, and precision diagnostics—are advancing its therapeutic potential. MUC1 exemplifies the shift toward novel tumor antigens in the next generation of ADC therapeutics.

Introduction: The ADC Landscape and the Emergence of “Unpopular Targets”

Antibody–drug conjugates (ADCs) have emerged as one of the most promising modalities in targeted cancer therapy, combining the selectivity of monoclonal antibodies with the potent cytotoxicity of small-molecule drugs. As of recent global statistics, over 140 ADC candidates are currently undergoing clinical trials, targeting a variety of well-established tumor-associated antigens such as HER2, TROP2, EGFR, CLDN18.2, CD19, and others. These popular targets have demonstrated clinical and commercial success, driving competition and innovation in ADC engineering and linker-payload optimization.

However, the growing saturation around these conventional targets has led researchers and biopharmaceutical companies to explore lesser-known or previously neglected targets—often referred to as “unpopular targets.” These include antigens that were once considered too challenging due to weak immunogenicity, poor specificity, or historical clinical failures. Technological advances in antibody engineering, linker chemistry, site-specific conjugation, and payload diversity have begun to overcome many of these limitations, widening the therapeutic window for difficult targets.

MUC1 (mucin-1) is one such target that has recently regained attention. Despite its complex biology and earlier development challenges, MUC1 is now recognized as a highly promising candidate due to its tumor-specific expression patterns and role in oncogenic signaling. The shift from conventional to unconventional targets in ADC development reflects a strategic transition in the field—from prioritizing established efficacy to unlocking untapped biological vulnerabilities.

This trend signals a new frontier in ADC research, one where innovation is not only driven by efficacy but also by target novelty and unmet clinical need.

Biological Characteristics and Oncogenic Role of MUC1

Mucin-1 (MUC1) is a transmembrane glycoprotein that belongs to the mucin family and plays a crucial role in epithelial cell protection, lubrication, and immune defense. First identified in 1982, MUC1 is primarily expressed on the apical surface of epithelial cells in various organs such as the lungs, pancreas, prostate, and breast. Its large extracellular domain is characterized by variable number tandem repeats (VNTRs), which are heavily O-glycosylated and provide the structural basis for its protective barrier function.

In cancer, MUC1 undergoes significant biochemical and spatial alterations. These include overexpression, abnormal glycosylation, and loss of cell polarity, which result in the redistribution of MUC1 across the entire cell surface and even into the cytoplasm. The tumor-associated form of MUC1 (TA-MUC1) exposes cryptic peptide and carbohydrate epitopes not present in healthy tissues, making it a viable target for antibody-based therapies such as ADCs.

Functionally, the MUC1-C terminal subunit is involved in oncogenic signal transduction. Upon cleavage and release of the MUC1-N domain, MUC1-C undergoes conformational changes that activate key cancer-promoting pathways including MAPK, PI3K/Akt, and Wnt/β-catenin. These pathways promote cell proliferation, survival, metastasis, and resistance to therapy. Moreover, MUC1 interacts with receptor tyrosine kinases and transcription factors, further integrating into the molecular network that supports tumor progression.

MUC1’s complex biology presents both challenges and opportunities for targeted therapies. Its dual nature—normal physiological role versus oncogenic transformation—necessitates precision in drug design, particularly in the context of ADC development where selectivity is critical.

MUC1 Expression Profile and Its Value as a Tumor Target

MUC1 is abnormally expressed in a wide range of epithelial-derived cancers, making it a highly attractive—yet historically underutilized—tumor-associated antigen for targeted therapy. In healthy tissues, MUC1 is expressed in a polarized manner, restricted to the apical surface of epithelial cells, where it contributes to mucosal defense and cellular homeostasis. However, in malignant tissues, MUC1 is not only overexpressed but also mislocalized across the entire cell membrane and even into the cytoplasm.

The overexpression of MUC1 is observed in several solid tumors, including non-small cell lung cancer (NSCLC), breast cancer, pancreatic ductal adenocarcinoma, prostate cancer, and epithelial ovarian cancer. In many of these cancers, MUC1 expression levels are 10 times higher than in normal tissue. This aberrant expression correlates with tumor aggressiveness, increased metastatic potential, recurrence, and resistance to chemotherapy, underscoring MUC1’s value as both a prognostic biomarker and a therapeutic target.

What further enhances the appeal of MUC1 as an ADC target is its tumor-specific glycoforms—altered glycosylation patterns that expose unique epitopes (e.g., Tn, STn antigens) not found in healthy cells. These exposed peptide and carbohydrate epitopes enable selective antibody binding, reducing off-target toxicity.

The heterogeneity in MUC1 expression among different cancer types and even within tumor subtypes presents a challenge but also a window for precision medicine. Companion diagnostic tools and stratification strategies can help identify MUC1-positive patients who may benefit most from ADC-based therapy. Thus, MUC1 is not only a marker of disease severity but also a gatekeeper for precision ADC targeting in oncology.

Current Status of MUC1-Targeted ADCs in Development

Despite its complex biology, MUC1 has garnered renewed interest as a target for antibody–drug conjugate (ADC) development. As of 2025, there are more than 25 MUC1-targeting ADC candidates globally, with at least 9 in clinical stages, including mono- and bispecific formats. These candidates aim to exploit the aberrant expression and tumor-specific glycoforms of MUC1 for selective delivery of potent cytotoxins.

One of the most advanced agents is DS-3939 (Daiichi Sankyo/Glycotope), developed using Daiichi’s DXd platform. It targets TA-MUC1 and carries a topoisomerase I inhibitor payload (exatecan derivative), with a drug-to-antibody ratio (DAR) of 8. Phase I/II trials began in 2023 for multiple solid tumors including NSCLC, breast, and pancreatic cancers.

DXC005 (DAC Biotech) is another MUC1-targeted ADC using a humanized monoclonal antibody linked to a Tubulysin analog. It is in Phase I clinical trials in China, following promising preclinical results presented at AACR 2024.

M1231 (Merck/Sutro Biopharma) is a bispecific ADC targeting both MUC1 and EGFR, using Sutro’s site-specific conjugation technology and Merck’s SEED antibody format. Its cytotoxic payload is Hemiasterlin, a potent microtubule inhibitor. Phase I trials have completed, but data are pending publication.

DM002 (Biocytogen/DaoBio) is a HER3×MUC1 bispecific ADC using either vcMMAE or a novel topoisomerase I payload (BLD1102). Preclinical models showed superior efficacy in resistant tumors. Clinical trials began in late 2024 in both China and the U.S.

While most MUC1-targeted ADCs remain in early-phase development, the variety of formats, payloads, and engineering strategies demonstrate the growing confidence in MUC1 as a viable and differentiated ADC target, particularly in tumors with high unmet needs.

Challenges, Strategies, and Future Directions

While MUC1 presents numerous opportunities as a tumor-associated antigen for ADC development, its clinical translation has faced significant challenges. One major obstacle is the shedding of the MUC1-N subunit, which acts as a decoy by binding to therapeutic antibodies in circulation, reducing tumor-specific drug delivery. Additionally, MUC1 is a self-antigen, which can limit immune response and create concerns regarding autoimmunity and tolerance.