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Technologies that can control both phenotype and yield in expanded cell products are highly desired. Here, we develop a new hydrogel scaffold for controlled T cell expansion with yields of up to 2000\u00d7 fold in two weeks, compared to other hydrogel constructs (\u2248250\u00d7) and Dynabeads (\u22481200\u00d7). Our 2D polyethylene glycol diacrylate (PEGDA) hydrogel scaffold is cross\u2010linked with streptavidin moieties to present various biotinylated ligands to cells with controlled hydrogel stiffness (PEGDA\u2010Strep). Using this platform, we demonstrate that combining substrate stiffness with adhesion receptor ligands (aLFA\u20101 or aCD2) dictates T cell activation and proliferation. On stiff substrates, these ligands drove expansions 49% (aLFA\u20101) and 68% (aCD2) greater than Dynabeads with comparable T cell products, preceded by elevated metabolic and transcriptional activity. Notably, while stiff substrates increased yield, soft substrates produced T cells with superior antigen\u2010specific killing selectivity. These findings highlight the role of mechanical sensing in T cell\u2010APC interactions and suggest improved manufacturing methods for adoptive T cell therapy (ACT).<\/jats:p>","DOI":"10.1002\/adma.202505965","type":"journal-article","created":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T14:31:39Z","timestamp":1767882699000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Tunable Enhancement of T Cell Expansion Through Modulation of Stiffness and Adhesion Receptor Engagement in an Engineered Hydrogel Platform"],"prefix":"10.1002","volume":"38","author":[{"given":"Niroshan","family":"Anandasivam","sequence":"first","affiliation":[{"name":"Department of Bioengineering University of California Berkeley  Berkeley USA"},{"name":"University of California, Berkeley and University of California, San Francisco Joint Graduate Program in Bioengineering University of California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rabia","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Bioengineering University of California Berkeley  Berkeley USA"},{"name":"University of California, Berkeley and University of California, San Francisco Joint Graduate Program in Bioengineering University of California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lordean","family":"Gustinvil","sequence":"additional","affiliation":[{"name":"Department of Bioengineering University of California Berkeley  Berkeley USA"},{"name":"University of California, Berkeley and University of California, San Francisco Joint Graduate Program in Bioengineering University of California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Rosenwasser","sequence":"additional","affiliation":[{"name":"Department of Bioengineering University of California Berkeley  Berkeley USA"},{"name":"University of California, Berkeley and University of California, San Francisco Joint Graduate Program in Bioengineering University of California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6329-4996","authenticated-orcid":false,"given":"Iain E.","family":"Dunlop","sequence":"additional","affiliation":[{"name":"Department of Materials Imperial College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8030-7672","authenticated-orcid":false,"given":"Derfogail","family":"Delcassian","sequence":"additional","affiliation":[{"name":"Department of Bioengineering University of California Berkeley  Berkeley USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,8]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2355"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.876339"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1039\/c6ib00233a"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2020.120584"},{"key":"e_1_2_9_6_1","first-page":"277","volume-title":"Engineering Platforms for T Cell Modulation","author":"Hickey J. 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