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Dysregulation of DEP domain containing 1 (DEPDC1) has been implicated in the pathogenesis of a variety of cancers. However, the role of DEPDC1 in PDAC is poorly understood. Here in this study, we identified that DEPDC1 was high-expressed in PDAC tissues compared with the adjacent normal pancreatic tissues, and its expression level was correlated with poor prognosis of PDAC. We also found that TCF7L2 up-regulated DEPDC1 expression by binding to its promoter sequence specifically. Further bioinfromatic and functional analysis demonstrated that the TCF7L2\/DEPDC1 axis can promote tumor cell proliferation and invasion by upregulating glycolysis. Glycolysis reprogramming influences the activation and function of immune cells, ultimately leading to immune escape and cancer progression. In consistent with this, our results showed that the TCF7L2\/DEPDC1 axis could form an immunosuppressive tumor microenvironment via promoting tumor glycolysis. Our findings revealed the critical role of TCF7L2\/DEPDC1 axis in the carcinogenesis and development of PDAC, which provided a promising therapeutic strategy to improve the prognosis of PDAC patients.<\/jats:p>","DOI":"10.1007\/s10238-026-02109-3","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T02:39:05Z","timestamp":1773887945000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TCF7L2\/DEPDC1 axis contributes to tumor progression by promoting cell proliferation, aerobic glycolysis, and immunosuppression in pancreatic cancer"],"prefix":"10.1007","volume":"26","author":[{"given":"Yesiboli","family":"Tasiheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayideng","family":"Kenjiabieke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuerzhati","family":"Tasiheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kawushaer","family":"Adilijiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"2109_CR1","unstructured":"National Cancer Institute. 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