Single-cell and spatially resolved atlas of pancreatic cancer reveals immunophenotypes associated with clinical outcome

Abstract Pancreatic ductal adenocarcinoma (PDAC), accounting for 90% of pancreatic neoplasms, is characterized by its poor prognosis, with a 5-year survival rate of only 12%. Most patients are diagnosed with metastatic or locally advanced disease, leaving only 15% eligible for curative resection. PDAC exhibits resistance to chemotherapy, targeted therapies, and immunotherapy, largely due to its highly heterogeneous tumor microenvironment (TME). In this study, we performed an integrative analysis of publicly available scRNA, spatial transcriptomics, and bulk RNA sequencing datasets to investigate the influence of TME composition and tumor architecture on PDAC progression, treatment response, and clinical outcomes. We identified TME subtypes with distinct cellular compositions, functional signatures, and immunomodulatory cell-cell interactions. Spatially distinct cellular niches and gene modules revealed heterogeneity across primary tumors and metastatic lesions. Deconvolution of these spatial niches in a large cohort of bulk RNA samples uncovered unique clusters associated with patient survival, providing novel insights into TME biology and its clinical implications. These findings underscore the importance of integrating multi-omics approaches to unravel the complexity of the PDAC TME and highlight its potential to inform therapeutic strategies and improve patient outcomes.