Targeting IRF7 to overcome gemcitabine resistance in pancreatic ductal adenocarcinoma

Interferon regulatory factor 7 (IRF7), a central transcription factor in interferon signaling, contributes to gemcitabine (GEM) resistance in pancreatic ductal adenocarcinoma (PDAC). We investigated how IRF7 mediates this resistance and explored strategies to overcome it. Elevated IRF7 expression was observed in GEM-refractory PDAC tissues. Functional assays revealed that IRF7 promotes GEM resistance by enhancing proliferation and suppressing apoptosis of PDAC cells. <i>In vivo</i>, IRF7 depletion combined with GEM treatment markedly inhibited tumor growth. Mechanistically, IRF7 activated transcription of CCL5, which facilitated glycolytic reprogramming and recruitment of immunosuppressive M2-like macrophages-both reinforcing GEM resistance. Temozolomide (TMZ) suppressed IRF7 transcriptional activity and, when combined with GEM, synergistically reduced tumor progression. These findings define IRF7 as a key regulator of chemotherapy response in PDAC and highlight the therapeutic potential of targeting the IRF7-CCL5 axis using TMZ to enhance GEM efficacy.