Pirfenidone antagonizes TGF-β1-mediated gabapentin resistance via reversal of desmoplasia and the ‘cold’ microenvironment in pancreatic cancer

Owing to the desmoplastic stroma constituted by cancer-associated fibroblasts (CAFs), few immune cells infiltrate the pancreatic ductal adenocarcinoma (PDAC). Gabapentin can impede the production of ketoacids by CAFs to support cancer cells. However, in our study, we discovered a dose-dependent increase in transforming growth factor β1 (TGF-β1) levels in cancer cells in response to gabapentin. This reverse increase of TGF-β1 contributes to 'Gabapentin-resistance’, leading to the antitumor effects on PDAC cell lines are negatively negotiated in the presence of pancreatic stellate cells. Pirfenidone synergistically inhibited the growth and apoptosis resistance of PDAC when combined with Gabapentin. In a mouse orthotopic PDAC model, Fe 3+ -mediated coordination nanodrugs, which contain gabapentin, pirfenidone and the natural polyphenol (EGCG), efficiently promoted the infiltration of naïve CD8 + T cells (CD44 low CD62L high ) and the accumulation of inflammatory CAFs (α-SMA low IL-6 high ). This led to a nearly two-fold increase in survival compared to the control. Furthermore, we identified a new subpopulation as Hmox1 high iCAFs following treatment with our nanodrugs. Hmox1 high iCAFs overexpressed the Cxcl10 receptor (Sdc4) and facilitated functional CD8 + T-cell infiltration through the Tnfsf9-Tnfrsf9 axis. Overall, our nanodrugs reshape the phenotype of CAFs and enhance functional CD8 + T-cell infiltration into tumors, holding the potential to be a safe and promising therapy for PDAC. • The elevated TGF-β1 after Gp treatment reversely attenuated its antitumor effect. • Combined application of Gp and pirfenidone could ameliorate ‘Gp-resistance’. • GEP increased naïve CD8+ T cells and iCAFs to reverse ‘Gp-resistance’. • Hmox1 high iCAFs stimulated CD8+ T-cell infiltration via Tnfsf9-Tnfrsf9 axis.