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Here, we develop a mathematical model that integrates spatial oxygen dynamics with continuous phenotypic adaptation to hypoxia and radiation, and use it to systematically compare radiotherapy protocols under a common normal-tissue toxicity constraint. Under spatially uniform oxygenation, we find that alternative fractionation schedules provide little improvement over standard-of-care protocols in normoxic conditions. Under moderate hypoxia, however, a distinct class of protracted schedules with longer inter-fraction intervals substantially increases time-to-progression, in some cases by up to twofold. This regime-dependent benefit is consistent with a shift in the balance between reoxygenation and selection for resistant phenotypes. When oxygen delivery is spatially heterogeneous, treatment outcomes depend strongly on the geometric organization of oxygen sources. Even with identical total oxygen supply, different spatial configurations lead to large variability in time-to-progression and can alter the relative ranking of radiotherapy protocols. These results show that radiotherapy effectiveness is not an intrinsic property of a treatment schedule alone, but emerges from its interaction with tumor microenvironmental structure and evolutionary dynamics. Incorporating both spatial heterogeneity and phenotypic adaptation may therefore be important for the consistent evaluation and design of fractionation strategies in heterogeneous tumors.<\/jats:p>","DOI":"10.1007\/s11538-026-01758-5","type":"journal-article","created":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T17:01:51Z","timestamp":1791046911000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Oxygenation and Spatial Heterogeneity Shape Radiotherapy Protocol Ranking Through Phenotypic Adaptation"],"prefix":"10.1007","volume":"88","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-2588-4168","authenticated-orcid":false,"given":"Francesco","family":"Albanese","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Chiari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello Edoardo","family":"Delitala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,3]]},"reference":[{"issue":"1","key":"1758_CR1","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1186\/s13014-019-1288-y","volume":"14","author":"JCL Alfonso","year":"2019","unstructured":"Alfonso JCL, Berk L (2019) Modeling the effect of intratumoral heterogeneity of radiosensitivity on tumor response over the course of fractionated radiation therapy. 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