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Studies demonstrate a strong correlation between nuclear factor kappa B (NF\u2010\u03baB) upregulation and prostate cancer malignancy. However, the mechanisms by which the mechanical stress within the TME activates NF\u2010\u03baB remain underexplored. This study developed a prostate cancer spheroid model using an in\u2010bath 3D bioprinting technique. Cancer spheroids were printed within a bespoke hydrogel bath with tunable stiffness, facilitating the investigation of the relationship between mechanical cues and oncogenic behavior. Increased hydrogel stiffness promoted spheroid compaction, induction of epithelial\u2013mesenchymal transition (EMT) and stemness programs, and elevated drug resistance. Transcriptomic analysis revealed that the phosphoinositide 3\u2010kinase (PI3K) pathway is most enriched under mechanical stress. Findings demonstrated that increased extracellular matrix stiffness activated PI3K\/NF\u2010\u03baB signaling through mechanotransduction. Pharmacological inhibition of PI3K suppressed NF\u2010\u03baB nuclear translocation and enhanced chemotherapy efficacy. The bespoke hydrogel effectively recapitulated the mechanical environment of prostate cancer, indicating the pivotal role of PI3K\/NF\u2010\u03baB signaling in regulating prostate cancer malignancy under mechanical stimulation. This suggests a promising therapeutic avenue for improving treatment outcomes.<\/jats:p>","DOI":"10.1002\/advs.202518295","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T06:36:27Z","timestamp":1767594987000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Mechanical Stimuli\u2010Induced Manipulation of Malignant Behavior in Bioprinted Cancer Microtissues via PI3K\/NF\u2010\u03baB Activation"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2494-6980","authenticated-orcid":false,"given":"Seok\u2010Hyeon","family":"Lee","sequence":"first","affiliation":[{"name":"School of Biomedical Convergence Engineering Pusan National University  Yangsan Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeongho","family":"Lee","sequence":"additional","affiliation":[{"name":"School of Biomedical Convergence Engineering Pusan 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