SLPI / FBW7 /c‐Myc Axis Reduces Gemcitabine Sensitivity in PDAC by Enhancing Glycolysis and Impairing NK Cell Immunity

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with dismal prognosis. Although gemcitabine works by directly inducing tumor cell death, as well as activating NK cell‐mediated antitumor immunity, its efficacy remains rather unsatisfying. Currently, biomarkers precisely ascertaining gemcitabine resistance in PDAC are unavailable; thus, it is of much urgency to identify biomarkers accurately predicting gemcitabine sensitivity and explore innovative targets for developing sensitization strategy. Secretory leukocyte protease inhibitor (SLPI) is overexpressed in several solid tumors, but its role in PDAC remains unclear. This study aims to elucidate the function and mechanism of SLPI in modulating gemcitabine sensitivity in PDAC. In this study, we found that SLPI was markedly upregulated in PDAC cell lines and tissues, inversely correlating with gemcitabine efficacy and survival outcome of patients. In vitro, SLPI overexpression significantly reduced PDAC cell sensitivity to gemcitabine‐induced direct cytotoxicity and NK cell‐mediated lysis through enhancing c‐Myc‐driven glycolysis, whereas SLPI knockdown generated the opposite effects. Mechanistically, SLPI could directly interact with c‐Myc protein, which disturbed the binding of E3 ubiquitin ligase FBW7 to c‐Myc and thereby prevented ubiquitination‐mediated c‐Myc degradation, resultantly increasing c‐Myc stability and expression. In vivo, SLPI knockdown substantially sensitized gemcitabine treatment to suppress PDAC growth, and this effect was at least partly dependent on NK cell‐mediated antitumor immunity. Totally, our findings support that SLPI may serve as a promising biomarker for predicting gemcitabine therapy response, and targeting SLPI may be an effective strategy to improve gemcitabine efficacy in PDAC patients. All procedures involving animals were conducted in compliance with institutional ethics regulations and approved by the Ethics Committee of the Second Hospital of Lanzhou University (Approval No. D2025‐434).