Tumor-derived GDF15 induces CCN3⁺ Schwann cells to promote cancer pain in pancreatic cancer

Tumor–neural crosstalk contributes to the remodeling of the tumor microenvironment, yet how tumors engage peripheral glial networks, particularly Schwann cells (SCs), to drive chronic pain remains unclear. Here, we identify a specialized cellular communication network factor 3-positive (CCN3⁺) SC subpopulation that promotes tumor innervation and contributes to pain in pancreatic ductal adenocarcinoma (PDAC). We demonstrate that cancer cell–derived growth differentiation factor 15 (GDF15) drives expansion of CCN3⁺ SCs and induces glycolytic reprogramming via the GDNF family receptor alpha-like (GFRAL) receptor. Mechanistically, GFRAL activation triggers the protein kinase B (AKT)–runt-related transcription factor 2 (RUNX2) cascade, upregulating the glycolytic enzyme muscle-type phosphofructokinase (PFKM) in CCN3⁺ SCs, which enhances tumor innervation and pain sensitization. Targeted inhibition of GDF15–GFRAL signaling in CCN3⁺ SCs significantly alleviates PDAC-associated pain. Together, these findings reveal a perineural–metabolic axis driven by glycolytic reprogramming in SCs and highlight a promising therapeutic strategy for PDAC-associated pain. Chronic pain in pancreatic ductal adenocarcinoma (PDAC) remains poorly understood. Here, the authors show that cancer-derived GDF15 drives the expansion of a specialized CCN3⁺ Schwann cell subpopulation, which in turn promotes sensory nerve sensitization and contributes to pain in PDAC.