Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, and current therapies show limited efficacy. Ligands and receptors of the TIGIT axis were analyzed using multicolor flow cytometry of tumor and blood samples, IHC from primary tumors, and single-cell RNA-Seq from primary tumors and liver metastasis from patients with various stages of PDAC. The effect of soluble and plate-bound Nectin-4 on T cell function was tested in vitro. Furthermore, patient-derived PDAC organoids were treated with the standard-of-care therapies FOLFIRINOX, gemcitabine plus paclitaxel, or the antibody-drug conjugate enfortumab vedotin. TIGIT expression was increased on tumor-infiltrating conventional T cells and Tregs compared with T cells from matched blood. Nectin-4 but not CD155 expression was associated with poor outcome. Nectin-4 was exclusively expressed by tumor cells and correlated with low immune infiltration. Notably, Nectin-4 inhibited T cell effector cytokine production in vitro. Targeting Nectin-4 with the antibody-drug conjugate enfortumab vedotin inhibited tumor growth in multiple patient-derived PDAC organoids. Collectively, our data underscore Nectin-4 as a potential novel therapeutic target and provide the rationale to test this agent in patients with PDAC.