Cancer‐Associated Fibroblast‐Derived Sphingosine‐1‐Phosphate Activates a MALL–SDC4 Axis to Facilitate Perineural Invasion in Pancreatic Cancer

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) frequently exhibits perineural invasion (PNI), a clinicopathologic feature strongly associated with local recurrence and poor survival, yet lacking effective targeted interventions. By integrating patient cohorts with single‐cell and bulk transcriptomics, multiplex immunofluorescence, and functional assays, this study defines a stromal‐tumor signaling axis facilitating neural invasion. Cancer‐associated fibroblasts (CAFs), particularly a myofibroblastic CAF‐enriched population, upregulate sphingosine kinase 1 (SPHK1) and increase secretion of sphingosine‐1‐phosphate (S1P), which activates sphingosine‐1‐phosphate receptor 3 (S1PR3)/JNK/JUN signaling to transcriptionally induce MAL‐like protein (MALL) in cancer cells. MALL binds to syndecan‐4 (SDC4) and promotes its recycling to the plasma membrane, thereby increasing surface SDC4 abundance. This MALL–SDC4 program promotes RhoA/phosphorylated myosin light chain 2 (p‐MLC2)‐dependent amoeboid motility and sensitizes cancer cells to Schwann cell‐derived pleiotrophin, strengthening directed neural invasion. Disruption of the axis through SPHK1 knockdown in CAFs, genetic perturbation of MALL or SDC4 in cancer cells, or adeno‐associated virus‐mediated SPHK1 or SDC4 knockdown in KPC ( Kras ^LSL‐G12D/+ ; Trp53 ^{LSL‐R172H/+} ; Pdx1 ‐Cre) mice significantly reduces PNI and tumor burden. These findings uncover a metabolite‐driven MALL–SDC4 program connecting stromal metabolism to neural invasion, and identify promising therapeutic targets for PDAC.