Type I Interferons Differentially Modulate Autophagy to Shape Gemcitabine Response in Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by poor prognosis and limited response to gemcitabine, the standard first-line chemotherapy. One major contributor to chemoresistance is autophagy, a process frequently upregulated in PDAC. In this study, we examined the ability of type I interferons (IFNα2b and IFNβ1a) to modulate autophagy and disturb tumor cell resistance to gemcitabine. PDAC cells were treated with increasing concentrations of IFNα2b or IFNβ1a, and cell proliferation was assessed by [³H]-thymidine incorporation. Apoptosis was evaluated by TUNEL staining following treatments with interferons and/or gemcitabine. Autophagy was analyzed by Western blot for LC3B and by quantifying autophagic flux using mCher-ry-EGFP-LC3B-transfected cells in the presence or absence of lysosomal inhibitors. We found that IFNα2b promoted autophagic flux and decreased gemcitabine-induced apop-tosis, indicating a cytoprotective role. In contrast, IFNβ1a inhibited autophagosome for-mation and significantly enhanced apoptosis in gemcitabine-treated cells. Our findings highlight the contrasting roles of IFNα2b and IFNβ1a in autophagy regulation and sug-gest that IFNβ1a, by inhibiting protective autophagy, may sensitize PDAC cells to chemo-therapy. This positions IFNβ1a as a promising adjuvant to overcome chemoresistance in PDAC treatment.