Cell surface plectin as a master regulator of tumor-immune interactions in pancreatic cancer

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.