{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T08:07:05Z","timestamp":1780387625194,"version":"3.54.1"},"reference-count":45,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82260555"],"award-info":[{"award-number":["82260555"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>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\u2010mediated 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\u00a0vitro, SLPI overexpression significantly reduced PDAC cell sensitivity to gemcitabine\u2010induced direct cytotoxicity and NK cell\u2010mediated lysis through enhancing c\u2010Myc\u2010driven glycolysis, whereas SLPI knockdown generated the opposite effects. Mechanistically, SLPI could directly interact with c\u2010Myc protein, which disturbed the binding of E3 ubiquitin ligase FBW7 to c\u2010Myc and thereby prevented ubiquitination\u2010mediated c\u2010Myc degradation, resultantly increasing c\u2010Myc stability and expression. In\u00a0vivo, SLPI knockdown substantially sensitized gemcitabine treatment to suppress PDAC growth, and this effect was at least partly dependent on NK cell\u2010mediated 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.<\/jats:p>\n                  <jats:p>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\u2010434).<\/jats:p>","DOI":"10.1111\/cas.70369","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T04:41:52Z","timestamp":1775104912000},"page":"1635-1650","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>SLPI<\/scp>\n                    \/\n                    <scp>FBW7<\/scp>\n                    \/c\u2010Myc Axis Reduces Gemcitabine Sensitivity in\n                    <scp>PDAC<\/scp>\n                    by Enhancing Glycolysis and Impairing\n                    <scp>NK<\/scp>\n                    Cell Immunity"],"prefix":"10.1111","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4134-5326","authenticated-orcid":false,"given":"Haofei","family":"Chen","sequence":"first","affiliation":[{"name":"The Second Hospital &amp; Clinical Medical School Lanzhou University  Lanzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of General Surgery, The Second Hospital &amp; Clinical Medical School Lanzhou University  Lanzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weixiong","family":"Zhu","sequence":"additional","affiliation":[{"name":"The Second Hospital &amp; Clinical Medical School Lanzhou University  Lanzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanxi","family":"Mu","sequence":"additional","affiliation":[{"name":"The Second Hospital &amp; Clinical Medical School Lanzhou University  Lanzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoqing","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Second Hospital &amp; Clinical Medical School Lanzhou University  Lanzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Second Hospital &amp; Clinical Medical School Lanzhou University  Lanzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusheng","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of General Surgery, The Second Hospital &amp; Clinical Medical School Lanzhou University  Lanzhou China"},{"name":"Gansu Province Hepatobiliary Pancreatic Disease Precision Diagnosis and Treatment Engineering Research Center Lanzhou University  Lanzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0529-7777","authenticated-orcid":false,"given":"Wence","family":"Zhou","sequence":"additional","affiliation":[{"name":"The Second Hospital &amp; Clinical Medical School Lanzhou University  Lanzhou China"},{"name":"Department of General Surgery, The Second Hospital &amp; Clinical Medical School Lanzhou University  Lanzhou China"},{"name":"Gansu Province Hepatobiliary Pancreatic Disease Precision Diagnosis and Treatment Engineering Research Center Lanzhou University  Lanzhou China"},{"name":"Gansu Province Key Laboratory of Environmental Oncology, the Second Hospital &amp; Clinical Medical School Lanzhou University  Lan zhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,1]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(25)00261-2"},{"key":"e_1_2_13_3_1","unstructured":"\u201cNational Comprehensive Cancer Network. 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