Keratan sulfate proteoglycans in pancreatic cancer: From stromal architects to potential therapeutic targets.

Pancreatic cancer features a dense desmoplastic stroma that drives therapeutic resistance and immune evasion. Traditionally viewed as inert scaffolds, keratan sulfate proteoglycans (KSPGs) now emerge as active signaling modulators within this tumor microenvironment. This review elucidates the multifaceted roles of KSPGs and their specific sulfation patterns in pancreatic ductal adenocarcinoma (PDAC). We detail how KSPG core proteins orchestrate collagen fibrillogenesis and tissue biomechanics, while highly sulfated keratan sulfate (KS) chains act as biochemical traps sequestering oncogenic ligands and chemokines. This biochemical interplay synergistically reprograms signaling cascades to govern tumor plasticity and metastasis. Crucially, KSPGs mediate immune exclusion by impeding CD8+ T cell infiltration and sustaining chronic inflammation via damage-associated molecular patterns (DAMPs). Finally, we highlight the translational potential of targeting KS sulfation via carbohydrate sulfotransferases (CHSTs) as a promising strategy for stromal normalization to overcome current therapeutic bottlenecks in PDAC.