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Existing in vitro models, including 2D cultures, animal systems, and Matrigel\u2010based organoids with fixed stiffness, fail to replicate physiologically relevant cell\u2013matrix interactions. Here, we developed a stiffness\u2010tunable microfluidic chip integrating sodium alginate\u2013decellularized ECM (SA\u2013dECM) hydrogels, enabling dynamic modulation of stiffness (2.90\u201313.31 kPa) to mimic clinical tumor conditions (\u223c7.94 kPa). Increased stiffness promotes chemoresistance, with gemcitabine IC\n                    <jats:sub>50<\/jats:sub>\n                    rising from 0.139 to 0.282 \u00b5\n                    <jats:sc>m<\/jats:sc>\n                    and cisplatin from 2.49 to 4.23 \u00b5\n                    <jats:sc>m<\/jats:sc>\n                    , alongside epithelial\u2010mesenchymal transition (EMT), as evidenced by a 64% reduction in E\u2010cadherin and a 6.35 fold increase in MMP2 expression. Co\u2010culture of ICC organoids and lung fibroblasts on\u2010chip further reveals that stiff matrices activate fibroblasts via TGF\u2010\u03b2 signaling, increasing \u03b1\u2010SMA and collagen deposition by 7.5 and 5.4 fold, respectively. These changes contribute to a pre\u2010metastatic niche, as confirmed by a 4.11 fold increase in invasive cell counts in PET membrane invasion assays. This dynamic stiffness\u2010tunable platform provides a robust in vitro model for studying stiffness\u2010driven invasion and pre\u2010metastatic niche formation in ICC and offers a valuable tool for personalized screening of anti\u2010fibrotic and chemosensitizing therapies.\n                  <\/jats:p>","DOI":"10.1002\/adhm.202503515","type":"journal-article","created":{"date-parts":[[2025,11,30]],"date-time":"2025-11-30T13:35:28Z","timestamp":1764509728000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Stiffness\u2010Tunable Hydrogel Microfluidic Chip Reveals the Role of Stiffness in Cholangiocarcinoma Invasion and Pre\u2010Metastatic Niche Formation"],"prefix":"10.1002","volume":"15","author":[{"given":"Lin","family":"Wu","sequence":"first","affiliation":[{"name":"College of Biomedical Engineering Sichuan University  Chengdu China"},{"name":"National Engineering Research Center for Biomaterials Sichuan 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