Spatial transcriptome profiling links SERPINA3 to nerve-associated immunosuppression in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy in which perineural invasion (PNI) represents a key indicator of poor prognosis; however, the underlying mechanisms of neuro-immune crosstalk remain incompletely understood. To address this, we integrated spatial transcriptomics, multiplex immunofluorescence, single-cell RNA sequencing, DRG neuron co-culture systems, CD8⁺ T cell cytotoxicity assays, orthotopic PDAC models, flow cytometry, and TCGA analyses. Spatial transcriptomics revealed elevated SERPINA3 expression and an immunosuppressive transcriptional program in tumor cells at the neural interface. In vivo, sensory denervation reduced tumor growth, decreased myeloid-derived suppressor cells and M2 macrophages, and enhanced TNF-α⁺ CD8⁺ T cell activity. Mechanistically, DRG-derived sensory neurons induced SERPINA3 expression in tumor cells, promoting resistance to CD8⁺ T cell-mediated apoptosis. Clinically, high SERPINA3 expression correlated with reduced cytotoxic immune infiltration and poorer overall survival. Collectively, these findings suggest that sensory neuron-induced SERPINA3 contributes to immune evasion in PDAC, highlighting its potential as a prognostic biomarker and a candidate target for remodeling the tumor immune microenvironment in preclinical settings.