ECM-responsive nanomedicine to enhance immunotherapy in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most treatment-resistant malignancies, primarily attributed to its dense and fibrotic extracellular matrix (ECM), which impedes both immune cell infiltration and drug delivery. Despite the remarkable success of immunotherapy in other cancer types, its efficacy in PDAC has been significantly compromised by the immune-exclusion barrier. Recent advancements in nanomedicine offer a compelling strategy to overcome this hurdle through the development of ECM-responsive delivery systems. These platforms are engineered to respond to ECM-specific triggers such as hyaluronidase or matrix metalloproteinases, enabling localized degradation of the tumor stroma while simultaneously releasing immunostimulatory agents. This review summarizes the unique ECM biology of PDAC, current limitations of immunotherapy, and recent breakthroughs in stimuli-responsive nanotechnology. This study also comprehensively discusses design principles, preclinical validation outcomes, translational challenges, and emerging strategies integrating ECM modulation with next-generation immune activation. ECM-responsive nanomedicine represents a transformative paradigm in stroma-immune co-engineering and offers a promising avenue for unlocking immunotherapy in PDAC.