{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T05:20:57Z","timestamp":1792819257956,"version":"4.5.0"},"posted":{"date-parts":[[2026,7,24]]},"group-title":"Bioengineering","reference-count":69,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/ NCI","award":["5R01CA276459"],"award-info":[{"award-number":["5R01CA276459"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\u03b3\u03b4 T-cells, which are predominantly enriched in epithelial tissues, have been used in cancer therapy because of their capacity for rapid cytotoxicity in an MHC-independent manner. Current paradigms are largely agnostic to the role of tissue mechanical cues in regulating \u03b3\u03b4 T-cell function. Here, we investigated the role of matrix viscoelasticity in modulating \u03b3\u03b4 T-cell migration, differentiation state, phenotype, and function. Using a tunable collagen-based gel system, we found that encapsulation in highly-elastic (slow-relaxing) matrices preserved a less differentiated phenotype, as evidenced by CD27 and CD45RA expression. Slow-relaxing matrices also increased expression of Fas and PD-1, while decreasing expression of CD11a. Despite increased PD-1 expression, these cells remained functional, as demonstrated by high levels of TNF-\u03b1 and IFN-\u03b3 relative to PD-1-negative cells. Proteomic analysis revealed that \u03b3\u03b4 T-cells respond to changes in viscoelasticity through actin remodeling and shifts in metabolic machinery. Overall, when compared to non-encapsulated cells (2D culture), encapsulated \u03b3\u03b4 T-cells showed increased expression of cytotoxic programs. Functionally, cells encapsulated in slow-relaxing gels showed improved control of tumor growth in an aggressive HCT116 tumor model. Together, these findings establish matrix viscoelasticity as an important regulator of post-thymic \u03b3\u03b4 T-cell differentiation and function.<\/jats:p>","DOI":"10.64898\/2026.07.23.740350","type":"posted-content","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T12:30:23Z","timestamp":1784896223000},"source":"Crossref","is-referenced-by-count":1,"title":["Viscoelastic Niches Shape \u03b3\u03b4 T-Cell Phenotype and Effector Function"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2500-4194","authenticated-orcid":false,"given":"Favour Omafuvwe","family":"Obuseh","sequence":"first","affiliation":[{"name":"Harvard-MIT Program in Health Sciences and Technology (HST), Cambridge, MA, USA"},{"name":"Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Chang","sequence":"additional","affiliation":[{"name":"School of Engineering and Applied Sciences (SEAS), Harvard University, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Price","sequence":"additional","affiliation":[{"name":"School of Engineering and Applied Sciences (SEAS), Harvard University, Cambridge, MA, USA"},{"name":"Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8900-2348","authenticated-orcid":false,"given":"Kyle","family":"Ruark","sequence":"additional","affiliation":[{"name":"School of Engineering and Applied Sciences (SEAS), Harvard University, Cambridge, MA, USA"},{"name":"Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania","family":"To","sequence":"additional","affiliation":[{"name":"School of Engineering and Applied Sciences (SEAS), Harvard University, Cambridge, MA, USA"},{"name":"Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3758-8285","authenticated-orcid":false,"given":"Leah","family":"Lourenco","sequence":"additional","affiliation":[{"name":"School of Engineering and Applied Sciences (SEAS), Harvard University, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3622-2003","authenticated-orcid":false,"given":"Bogdan","family":"Budnik","sequence":"additional","affiliation":[{"name":"Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6299-1194","authenticated-orcid":false,"given":"David","family":"Mooney","sequence":"additional","affiliation":[{"name":"School of Engineering and Applied Sciences (SEAS), Harvard University, Cambridge, MA, USA"},{"name":"Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026072720400675000_2026.07.23.740350v1.1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.iy.11.040193.003225"},{"key":"2026072720400675000_2026.07.23.740350v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3384"},{"key":"2026072720400675000_2026.07.23.740350v1.3","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41392-023-01653-8","article-title":"\u03b3\u03b4 T cells: origin and fate, subsets, diseases and immunotherapy","volume":"8","year":"2023","journal-title":"Sig Transduct Target Ther"},{"key":"2026072720400675000_2026.07.23.740350v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05593-1"},{"key":"2026072720400675000_2026.07.23.740350v1.5","doi-asserted-by":"crossref","unstructured":"Lo Presti, E. , Dieli, F. & Meraviglia, S. 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