IGF2BP2 stabilized by USP7 promotes cancer-associated fibroblast activation and attenuates gemcitabine sensitivity in PDAC.

N6-Methyladenosine (m6A) modification is a prevalent alteration in RNA, influencing stability, localization, and translation. The m6A reader IGF2BP2 stabilizes various mRNA transcripts of oncogenic proteins and has been extensively implicated in various tumors. Intriguingly, in pancreatic ductal adenocarcinoma (PDAC), IGF2BP2 maintains its protein stability despite the elevated autophagic activity, suggesting the existence of regulatory mechanisms that counteract IGF2BP2 degradation in PDAC. Herein, we explore the crosstalk between m6A modification and protein homeostasis, particularly the protein stability of IGF2BP2 under excessive activation of autophagic flux. Mechanistically, we show that deubiquitinase USP7 acts on IGF2BP2, which enhances the stability of IGF2BP2 by reversing its K33-linked polyubiquitin chains, thereby preventing its degradation via the autophagy-lysosome pathway. Accumulated IGF2BP2 stabilizes PDGFA mRNA, activating myofibroblastic cancer-associated fibroblasts (myCAFs) through PDGFR interaction, which promotes resistance to gemcitabine. These findings uncover the USP7/IGF2BP2/PDGFA axis as a critical regulatory pathway in PDAC progression and chemoresistance.