Biomarker-Driven Strategies for Stromal Reprogramming in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal, partly because its dense, heterogeneous stroma restricts drug delivery, promotes immune exclusion, and supports therapeutic resistance. Stromal targeting has, therefore, evolved from broad depletion towards biomarker-guided reprogramming and normalization strategies that aim to restore vascular function, improve intratumoral drug penetration, and enhance antitumor immunity. This review summarizes evidence on stromal biomarkers with prognostic or predictive value, including tumor–stroma ratio, fibrosis burden, cancer-associated fibroblast states, extracellular matrix stiffness, vascular accessibility, and spatial immune features. It also examines emerging therapeutic approaches to reprogram the PDAC stroma, such as repurposed drugs, immune–stromal modulators, metabolic interventions, and advanced delivery systems. Emphasis is placed on clinically or translationally supported strategies, including CXCR4, CD40, CD73, vitamin D receptor agonism, matrix remodeling, and biomarker-driven stratification. Overall, PDAC stroma is a dynamic therapeutic target, requiring composite biomarkers and rational combinations with chemotherapy, immunotherapy, and delivery-enhancing strategies.