A TROP2-targeting aptamer enables selective drug delivery and potent antitumor activity in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) remains difficult to treat, highlighting the need for strategies that selectively deliver cytotoxic agents to tumor cells. Trophoblast cell-surface antigen 2 (TROP2) has been proposed as a candidate therapeutic target in PDAC, but non-antibody-based delivery formats remain underexplored. Using protein-SELEX, we identified T17, a high-affinity aptamer that specifically binds to TROP2, and conjugated it to monomethyl auristatin E through an MC-Val-Cit-PAB linker to generate the aptamer-drug conjugate T17-M. Preclinical evaluation in cellular and animal models showed that T17-M retained TROP2-dependent binding, underwent clathrin-mediated internalization and lysosomal processing, and suppressed tumor growth in cell-line-derived and patient-derived xenografts. T17-M also reduced liver metastasis and induced calreticulin exposure, ATP release, and HMGB1 secretion, consistent with immunogenic cell death. In immunocompetent models, T17-M promoted dendritic-cell activation and CD8 + T cell infiltration, while its combination with PD-1 blockade further enhanced tumor control and prolonged survival. These findings provide preclinical proof-of-concept for T17-M as an alternative TROP2-targeted drug-delivery strategy for PDAC.