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.