Cancer-associated fibroblasts secrete FGF5 to inhibit ferroptosis to decrease cisplatin sensitivity in nasopharyngeal carcinoma through binding to FGFR2

Abstract Cisplatin (DDP)-based chemoradiotherapy is one of the standard treatments for nasopharyngeal carcinoma (NPC). However, the sensitivity and side effects of DDP to patients remain major obstacles for NPC treatment. This research aimed to study DDP sensitivity regulated by cancer-associated fibroblasts (CAFs) through modulating ferroptosis. We demonstrated that DDP triggered ferroptosis in NPC cells, and it inhibited tumor growth via inducing ferroptosis in xenograft model. CAFs secreted high level of FGF5, thus inhibiting DDP-induced ferroptosis in NPC cells. Mechanistically, FGF5 secreted by CAFs directly bound to FGFR2 in NPC cells, leading to the activation of Keap1/Nrf2/HO-1 signaling. Rescued experiments indicated that FGFR2 overexpression inhibited DDP-induced ferroptosis, and CAFs protected against DDP-induced ferroptosis via FGF5/FGFR2 axis in NPC cells. In vivo data further showed the protective effects of FGF5 on DDP-triggered ferroptosis in NPC xenograft model. In conclusion, CAFs inhibited ferroptosis to decrease DDP sensitivity in NPC through secreting FGF5 and activating downstream FGFR2/Nrf2 signaling. The therapeutic strategy targeting FGF5/FGFR2 axis from CAFs might augment DDP sensitivity, thus decreasing the side effects of DDP in NPC treatment.