Boron neutron capture therapy (BNCT) offers a precision chemoradiation strategy by delivering boron compounds like p-borophenylalanine (BPA) into tumors via the L-type amino acid transporter 1 (LAT1). However, its effectiveness is constrained in tumors with low LAT1 expression. To expand the applicability of BNCT, we have developed a novel approach that leverages tumor-specific biomarkers, focusing on cancers that exhibit high levels of the validated glycan marker CA19-9. Using The Cancer Genome Atlas (TCGA) datasets, we explored the transcriptomic landscape to identify tumors with low LAT1 expression yet high levels of CA19-9. This analysis revealed that fucosyltransferase 3 (FUT3), the key enzyme driving CA19-9 synthesis, is upregulated in pancreatic, biliary, and ovarian cancers. Building on this insight, we designed a new boron agent, fucose-BSH, tailored to preferentially target CA19-9–positive tumors. Its chemical properties, pharmacokinetic behavior, tissue distribution, and therapeutic efficacy were systematically assessed in vitro and in xenograft models, with direct comparisons made to the established boron carrier, BPA. Fucose-BSH exhibited markedly higher boron accumulation in Cell lines positive for CA19-9, including HuCCT-1, AsPC-1, Panc 04.03, and HSKTC, and OVISE) than in the CA19-9–negative PANC-1 cell line. In HuCCT-1 xenograft models, boron levels in tumors reached 36.2 ppm, yielding a tumor-to-normal tissue ratio of 2.1 and surpassing the performance of BPA. Following neutron irradiation, BNCT mediated by fucose-BSH resulted in greater than 80% inhibition of tumor growth. Importantly, fucose-BSH maintained its therapeutic effectiveness in LAT1-deficient models, where BPA showed no efficacy, thereby verifying its LAT1-independent mechanism of targeting. This work introduces a precision BNCT strategy that exploits CA19-9 as a tumor-specific glycan for targeted boron delivery. The novel agent fucose-BSH demonstrates potential to extend BNCT applicability to LAT1-low cancers, including those of the pancreas, biliary tract, and ovary. These results offer a clinically relevant framework for tumor marker–guided chemoradiation and pave the way for translational implementation of BNCT. Moreover, this approach could facilitate the development of companion diagnostics and enable precision patient stratification in current and future BNCT clinical studies. Cancers characterized by high CA19-9 expression, including pancreatic, biliary, and ovarian malignancies, are linked to poor outcomes and limited responsiveness to existing treatments. In this study, we introduce a tumor marker–guided approach to boron neutron capture therapy (BNCT), exploiting the biology of CA19-9 glycans for selective tumor targeting using fucose-BSH, a novel boron agent. Through transcriptomic analyses and preclinical evaluation, fucose-BSH demonstrated effective LAT1-independent boron delivery, robust BNCT-induced cytotoxicity, and preferential accumulation in CA19-9–positive models. These results highlight a precision chemoradiation strategy that expands BNCT to previously untreatable tumors and provides a clinically actionable framework for patient selection and therapeutic development in CA19-9–expressing cancers.
