Precision targeting of stromal states in pancreatic cancer: a clinical perspective

Desmoplastic stroma defines pancreatic ductal adenocarcinoma (PDAC), a highly lethal malignancy. This stroma drives tumor progression, immune evasion, drug resistance, and poor drug delivery. Although targeting tumor stroma has shown preclinical promise, most clinical trials have failed due to limited translational success. A major hurdle is the stroma's extreme heterogeneity and dynamic nature, meaning uniform treatments fail. Emerging evidence supports the existence of distinct 'stromal states' with differential biological functions and therapeutic vulnerabilities. Characterizing these states provides a framework to stratify patients and guide precise, stroma-directed therapies. This review summarizes the clinical landscape of PDAC stroma-targeting strategies, discusses distinct stromal states, and outlines emerging opportunities to exploit the stroma as a therapeutic axis in PDAC to improve clinical trial outcomes.