Tumor microenvironment subtyping in pancreatic ductal adenocarcinoma: New avenues for personalized therapeutic strategies

In the past decade, single-cell-resolved approaches have uncovered the extensive heterogeneity of pancreatic ductal adenocarcinoma (PDAC), reshaping our understanding of this complex solid tumor. PDAC entities exhibit both intra- and inter-tumor heterogeneity at the tumor and stromal levels, translating into distinct ecosystems and functions, ultimately impacting disease progression and treatment response. Increasing evidence highlights how specific genetic alterations drive unique tumor microenvironment landscapes, affecting fibroblast programming, immune cell contexture and extracellular matrix remodeling. In this review, we emphasize the importance of deciphering and stratifying heterogeneous tumor-stroma networks and provide an overview on the intricate crosstalk linking tumor identity and stromal phenotype. We further discuss the concept of multicellular subtyping and the role of spatial organization in shaping patient outcomes to refine prognostic and therapeutic stratification. Lastly, we explore existing and potential therapeutic strategies aimed at targeting both tumor-intrinsic and stromal-extrinsic vulnerabilities, offering insights into approaches that could enhance the efficacy of tailored treatment schemes. By integrating these perspectives, we aim to provide a comprehensive framework for advancing precision medicine in PDAC.