{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T21:20:20Z","timestamp":1791408020583,"version":"4.3.3"},"reference-count":42,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T00:00:00Z","timestamp":1768694400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"T.T. and W.F. Chao Foundation"},{"DOI":"10.13039\/100006988","name":"John S. Dunn Research Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100006988","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Houston Methodist Dyer Fellowship Award"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) is highly lethal, and many patients cannot undergo curative surgery due to frailty. Multimodal prehabilitation: combining exercise, nutrition, and psychological support improves functional readiness, but its biological impact on the PDAC tumor microenvironment (TME) is unclear. In this exploratory pilot study, we profiled resected PDAC tissues from prehabilitation-treated patients and matched controls using NanoString GeoMx Digital Spatial Profiling across immune, tumor, and stromal compartments (n = 4). Transcriptomic signatures were analyzed via differential expression, pathway enrichment, and MCP-counter deconvolution; protein-level validation used multiplex immunofluorescence (n = 8). Ligand\u2013receptor modeling assessed cell\u2013cell communication, and prognostic relevance was evaluated in TCGA-PDAC (n = 178). Prehabilitation was associated with increased NK-cell cytotoxicity, interferon response, and chemokine recruitment, as well as higher neutrophil signatures (p &lt; 0.01) and reduced fibroblast signatures (p &lt; 0.05). Tumor regions showed lower MAPK and PI3K\/AKT activity, while stroma exhibited decreased TGF-\u03b2 and Wnt signaling. Immunofluorescence confirmed neutrophil infiltration and reduced fibroblast density. TCGA analysis linked neutrophil-high\/fibroblast-low profiles to longer survival (1044.6 vs. 458.7 days, p = 0.0052). These findings suggest prehabilitation may promote a more immune-active, less fibrotic TME in PDAC, resembling transcriptional states associated with improved survival. Prospective studies integrating biological and clinical endpoints are warranted.<\/jats:p>","DOI":"10.3390\/ijms27020943","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T09:24:34Z","timestamp":1768901074000},"page":"943","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Prehabilitation as a Biologically Active Intervention Is Associated with the Remodeling of the Pancreatic Tumor-Immune Microenvironment"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3534-0235","authenticated-orcid":false,"given":"Renee","family":"Stubbins","sequence":"first","affiliation":[{"name":"Houston Methodist Neal Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Vasquez","sequence":"additional","affiliation":[{"name":"Advanced Cellular and Tissue Microscopy Core, Houston Methodist Research Institute, Houston Methodist Neal Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blythe K.","family":"Gorman","sequence":"additional","affiliation":[{"name":"Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX 77030, USA"},{"name":"Department of Pathology and Laboratory Medicine, Weill Cornell Medicine at Houston Methodist, Houston, TX 77030, USA"},{"name":"Department of Pathology and Genomic Medicine, Texas A&M University Naresh K. Vashisht College of Medicine, Houston Campus, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Zambelas","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, TX 77030, USA"},{"name":"Neuroscience PhD Program, Weill Cornell Medicine at Houston Methodist, Houston TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelvin","family":"Allenson","sequence":"additional","affiliation":[{"name":"Department of Surgery, Houston Methodist Hospital, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atiya","family":"Dhala","sequence":"additional","affiliation":[{"name":"Department of Surgery, J.C. Walter Jr. Transplant Center, Center for Critical Care, Houston Methodist Hospital, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjuan","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8991-7824","authenticated-orcid":false,"given":"Hong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Houston Methodist Neal Cancer Center, Houston, TX 77030, USA"},{"name":"Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, TX 77030, USA"},{"name":"Advanced Cellular and Tissue Microscopy Core, Houston Methodist Research Institute, Houston Methodist Neal Cancer Center, Houston, TX 77030, USA"},{"name":"Department of Medicine, Weill Cornell Medicine at Houston Methodist, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9188-6502","authenticated-orcid":false,"given":"Stephen","family":"Wong","sequence":"additional","affiliation":[{"name":"Houston Methodist Neal Cancer Center, Houston, TX 77030, USA"},{"name":"Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, TX 77030, USA"},{"name":"Advanced Cellular and Tissue Microscopy Core, Houston Methodist Research Institute, Houston Methodist Neal Cancer Center, Houston, TX 77030, USA"},{"name":"Neuroscience PhD Program, Weill Cornell Medicine at Houston Methodist, Houston TX 77030, USA"},{"name":"Department of Medicine, Weill Cornell Medicine at Houston Methodist, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,18]]},"reference":[{"key":"ref_1","first-page":"17","article-title":"Cancer statistics, 2023","volume":"73","author":"Siegel","year":"2023","journal-title":"CA Cancer J. 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