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Here, we develop a mechano\u2013electro\u2013osmotic model integrating metabolic gradients, ion transport, and cellular mechanics to explain residual solid stress emergence in tumor spheroids, common models of solid tumors. We show that solid stress arises predominantly from osmotic cell swelling driven by metabolic deprivation and ion accumulation, rather than proliferation. This mechanism generates a characteristic stress architecture: isotropic compression in the hypoxic core balanced by peripheral tangential tension, causing pronounced cell and nuclear deformation. The resulting nuclear strain provides a mechanical basis for DNA damage and genomic instability implicated in disease progression and treatment resistance. We validate these predictions in breast cancer using MDA-MB-231 spheroids and patient-derived ductal carcinoma in situ lesions, and corroborate them across published spheroid models and in vivo and ex vivo tumors spanning additional cancer types. Our findings link tumor metabolism to clinically relevant mechanical stresses, suggesting opportunities to target osmotic and metabolic pathways to mitigate solid stress and improve therapeutic outcomes.<\/jats:p>","DOI":"10.64898\/2026.02.05.704098","type":"posted-content","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T04:45:10Z","timestamp":1770612310000},"source":"Crossref","is-referenced-by-count":0,"title":["Metabolic starvation\u2013induced cell swelling drives solid stress in tumors"],"prefix":"10.64898","author":[{"given":"Mohammad","family":"Dehghany","sequence":"first","affiliation":[{"name":"Center for Engineering Mechanobiology, University of Pennsylvania, PA, USA"},{"name":"Department of Materials Science and Engineering, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vivek","family":"Sharma","sequence":"additional","affiliation":[{"name":"Center for Engineering Mechanobiology, University of Pennsylvania, PA, USA"},{"name":"Department of Mechanical Engineering, University of Pennsylvania, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akash Samuel","family":"Annie-Mathew","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Children\u2019s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"name":"Department of Bioengineering, University of Pennsylvania, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrei","family":"Zakharov","sequence":"additional","affiliation":[{"name":"Center for Engineering Mechanobiology, University of Pennsylvania, PA, USA"},{"name":"Department of Materials Science and Engineering, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom C.","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guilherme Pedreira","family":"de Freitas Nader","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Children\u2019s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vivek B.","family":"Shenoy","sequence":"additional","affiliation":[{"name":"Center for Engineering Mechanobiology, University of Pennsylvania, PA, USA"},{"name":"Department of Materials Science and Engineering, University of Pennsylvania, Philadelphia, PA, USA"},{"name":"Department of Mechanical Engineering, University of Pennsylvania, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026021107300678000_2026.02.05.704098v1.1","unstructured":"Nia, H.T. , et al., In vivo compression and imaging in mouse brain to measure the effects of solid stress. 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