{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:29:18Z","timestamp":1786969758394,"version":"build-2736575974"},"reference-count":40,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["GL 893\/1-2"],"award-info":[{"award-number":["GL 893\/1-2"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["KA 2679\/3-2"],"award-info":[{"award-number":["KA 2679\/3-2"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"award":["GL 893\/1-2"],"award-info":[{"award-number":["GL 893\/1-2"]}],"id":[{"id":"https:\/\/ror.org\/018mejw64","id-type":"ROR","asserted-by":"publisher"}]},{"award":["KA 2679\/3-2"],"award-info":[{"award-number":["KA 2679\/3-2"]}],"id":[{"id":"https:\/\/ror.org\/018mejw64","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: High linear energy transfer (LET) carbon ions achieved more effective and biologically robust tumor control than photons in preclinical prostate cancer models; however, the longitudinal development of histopathological parameters remains insufficiently characterized, limiting the selection of the optimal treatment modality in patients. This study analyzed the temporal histological patterns after isoeffective photon, proton, and carbon ion irradiations. Methods: Two Dunning R3327 prostate carcinoma sublines (H, HI) grown subcutaneously in male Copenhagen rats received single-fraction isoeffective curative photon or carbon ion doses. For HI-tumors, the effectiveness of isoeffective curative proton doses and isoeffective subcurative photon and carbon ion doses was additionally investigated. Tumors were collected prior and up to 3 weeks after irradiation and processed for quantitative histology of proliferation (BrdU), DNA damage (\u03b3H2AX), hypoxia (pimonidazole), vascular (CD31), and immune cell (CD3, CD68) markers. Results: All modalities induced an early peak in \u03b3H2AX+ tumor cells and a pronounced suppression of BrdU+ cells, with more sustained effects after isoeffective carbon ions doses, particularly in the HI-tumors. These findings, however, differed strongly between hypoxic and oxic micro-environments. Vascular parameters, diffusion distances, and global and compartment-specific hypoxic fractions showed distinct temporal dynamics between photons and carbon ions in HI-tumors, whereas H-tumors exhibited more moderate and reversible changes. At curative carbon ion doses, there was a late rebound of BrdU-positive tumor cells and increased CD68+ macrophage accumulation in chronically hypoxic regions. CD3+ T cells showed a biphasic decrease-recovery pattern in HI-tumors largely independent of radiation quality and oxygenation. Conclusions: Longitudinal histology revealed modality- and tumor-line-specific trajectories of tumor, vascular, hypoxic, and immune responses after isoeffective photon, proton, and carbon ion irradiations in prostate carcinoma. The more persistent tumor cell damage and distinct vascular response, together with late proliferative and macrophage rebounds under chronic hypoxia after carbon ions, provide mechanistic support for the increased biological effectiveness and highlight hypoxia-driven repopulation and inflammation as key processes.<\/jats:p>","DOI":"10.3390\/cancers18162653","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:01:26Z","timestamp":1786968086000},"page":"2653","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Longitudinal Tumor, Vascular, and Immune Cell Response in Two Rat Prostate Carcinomas After Isoeffective Photon, Proton, and Carbon Ion Irradiation: Impact of Linear Energy Transfer, Dose Level, and Hypoxia"],"prefix":"10.3390","volume":"18","author":[{"given":"Michaela","family":"Schmitt","sequence":"first","affiliation":[{"name":"Division of Medical Physics in Radiation Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"},{"name":"Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany"},{"name":"Heidelberg Institute for Radiation Oncology (HIRO) and National Center for Radiation Research in Oncology (NCRO), 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ina","family":"Kurth","sequence":"additional","affiliation":[{"name":"Heidelberg Institute for Radiation Oncology (HIRO) and National Center for Radiation Research in Oncology (NCRO), 69120 Heidelberg, Germany"},{"name":"Division of Radiooncology\/Radiobiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christin","family":"Glowa","sequence":"additional","affiliation":[{"name":"Division of Medical Physics in Radiation Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"},{"name":"Heidelberg Institute for Radiation Oncology (HIRO) and National Center for Radiation Research in Oncology (NCRO), 69120 Heidelberg, Germany"},{"name":"Department of Radiation Oncology and Radiotherapy, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Dittrich","sequence":"additional","affiliation":[{"name":"Heidelberg Institute for Radiation Oncology (HIRO) and National Center for Radiation Research in Oncology (NCRO), 69120 Heidelberg, Germany"},{"name":"Division of Radiooncology\/Radiobiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosemarie","family":"Euler-Lange","sequence":"additional","affiliation":[{"name":"Heidelberg Institute for Radiation Oncology (HIRO) and National Center for Radiation Research in Oncology (NCRO), 69120 Heidelberg, Germany"},{"name":"Division of Radiooncology\/Radiobiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4695-0816","authenticated-orcid":false,"given":"Stephan","family":"Brons","sequence":"additional","affiliation":[{"name":"Heidelberg Institute for Radiation Oncology (HIRO) and National Center for Radiation Research in Oncology (NCRO), 69120 Heidelberg, Germany"},{"name":"Heidelberg Ion Beam Therapy Center (HIT), 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Peschke","sequence":"additional","affiliation":[{"name":"Division of Medical Physics in Radiation Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"},{"name":"Heidelberg Institute for Radiation Oncology (HIRO) and National Center for Radiation Research in Oncology (NCRO), 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7194-8136","authenticated-orcid":false,"given":"Christian P.","family":"Karger","sequence":"additional","affiliation":[{"name":"Division of Medical Physics in Radiation Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"},{"name":"Heidelberg Institute for Radiation Oncology (HIRO) and National Center for Radiation Research in Oncology (NCRO), 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/nrclinonc.2013.79","article-title":"Charged particle therapy\u2014Optimization, challenges and future directions","volume":"10","author":"Loeffler","year":"2013","journal-title":"Nat. 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