Abstract Pancreatic ductal adenocarcinoma (PDAC) is the third deadliest cancer in the United States, with a five-year survival rate of only 13%, and is projected to become the second leading cause of cancer-related mortality by 2030. Despite advances in personalized medicine, therapeutic options for PDAC remain extremely limited, underscoring the need for new, clinically actionable targets. In 2008, Kelly et al. utilized a phage-display-based functional proteomics platform that identified plectin, a cytolinker protein normally restricted to the cytoplasm, as aberrantly mislocalized to the plasma membrane of PDAC cells. This cell-surface form of plectin (CSP) has since been detected across multiple malignancies, including PDAC, ovarian carcinoma, and cholangiocarcinoma, while remaining cytoplasmic in normal tissues. Functional studies using an anti-CSP monoclonal antibody (mAb) revealed that CSP supports pro-tumorigenic behaviors such as proliferation, migration, and invasion. A recent early-phase clinical trial (NCT05074472) evaluating an anti-CSP mAb in CSP-positive cancers demonstrated that CSP-targeted therapy is both safe and clinically feasible. To further resolve the molecular and immunologic roles of CSP, we analyzed transcriptomic data from human PDAC bulk and single-cell RNA-sequencing datasets. CSP-high tumors exhibited suppression of pro-inflammatory immune pathways and reduced infiltration of cytotoxic immune populations—hallmarks of the immune-cold PDAC microenvironment. Anti-CSP mAb treatment in vivo promoted infiltration of CD4+ and CD8+ T cells, reduced tumor burden, and generated a durable effector-memory response capable of preventing tumor re-challenge. Collectively, these findings provide the first direct evidence that CSP functions as an immune suppressor in PDAC. Moreover, therapeutic blockade of CSP can restore anti-tumor immunity in this notoriously immunoresistant cancer, offering a promising avenue for personalized treatment strategies for patients with historically few effective options. Citation Format: Cody L. Wolf, Roxanne K. Ruiz, Sokchea Khou, Robert Cornelison, Edward Stelow, Karl M. Kowalewski, Matthew J. Lazzara, Amanda Poissonnier, Timothy N. Bullock, Lisa M. Coussens, Kimberly A. Kelly. Cell surface plectin as a master regulator of tumor-immune interactions in pancreatic cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6582.
Wolf et al. (Fri,) studied this question.