{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T19:02:46Z","timestamp":1790622166152,"version":"4.1.0"},"reference-count":39,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Neoadjuvant therapy (NAT) is increasingly used for pancreatic ductal adenocarcinoma (PDAC); yet most patients only achieve partial response. Pathological treatment response grading focuses on assessing residual tumor burden, often overlooking changes in tumor microenvironment (TME). To address this gap, we compared tumor cells and TME of 13 NAT\u2010na\u00efve and 23 post\u2010NAT PDACs using integrated spatial pathomics and transcriptomics, with validation in an independent single\u2010cell spatial dataset. NAT significantly reduced tumor burden (14.7%\u20136.2%,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.004), but systemic comparison of 13 cytomorphometric features of tumor cells alone did not reliably distinguish between na\u00efve and NAT cases. In contrast, NAT profoundly remodeled TME by increasing cancer\u2010associated fibroblast (CAF) and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell densities, promoting CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell\u2010tumor cell proximity and fibrosis, reducing tumor\u2010associated neutrophils, and redistributing tertiary lymphoid structures (TLSs). Spatial transcriptomics shows NAT induced apoptosis, DNA\u2010damage response, and AGC\u2010kinase (S_TK_X) signaling in tumor cells, and upregulated complement pathway, p53 signaling, and cellular senescence program in TME. Cross\u2010platform single\u2010cell spatial analysis revealed decreased regulatory T cells (Treg) and a shift from myofibroblastic (mCAF) to inflammatory CAF (iCAF). Importantly, post\u2010NAT patients with more fibrosis had longer overall survival (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.02), and higher B\u2010cell density showed a favorable trend (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.06). Together, these results suggest that beyond tumor debulking, NAT induces a coordinated TME remodeling characterized by fibroblast reprogramming, matrix fibrosis, and immune spatial reorganization. Incorporating assessment of NAT\u2010induced stromal and immune changes into TRG may improve prognostication and guide more precise therapy in post\u2010NAT PDAC.\n                  <\/jats:p>","DOI":"10.1111\/cas.70320","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T07:40:27Z","timestamp":1768376427000},"page":"1167-1177","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Neoadjuvant Therapy\u2010Induced Remodeling in Pancreatic Ductal Adenocarcinoma: Multimodal Spatial Analysis and Prognosis"],"prefix":"10.1111","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0810-7254","authenticated-orcid":false,"given":"Xiaofei","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pathology New York University Grossman Long Island School of Medicine  Long Island New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruoxin","family":"Lan","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Data Science Tulane University School of Public Health and Tropical Medicine  New Orleans Louisiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danting","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Data Science Tulane University School of Public Health and Tropical Medicine  New Orleans Louisiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjun","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington School of Medicine  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonu","family":"Kalyan","sequence":"additional","affiliation":[{"name":"Department of Pathology New York University Grossman Long Island School of Medicine  Long Island New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Momin","family":"Iqbal","sequence":"additional","affiliation":[{"name":"Department of Pathology New York University Grossman Long Island School of Medicine  Long Island New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Washington School of Medicine  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerry","family":"Zhang","sequence":"additional","affiliation":[{"name":"Skyline High School  Sammamish Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iman","family":"Hanna","sequence":"additional","affiliation":[{"name":"Department of Pathology New York University Grossman Long Island School of Medicine  Long Island New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mala","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Pathology New York University Grossman Long Island School of Medicine  Long Island New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaohui L.","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pathology New York University Grossman Long Island School of Medicine  Long Island New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiguo","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology New York University Grossman Long Island School of Medicine  Long Island New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Melamed","sequence":"additional","affiliation":[{"name":"Department of Pathology New York University Grossman Long Island School of Medicine  Long Island New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Shusterman","sequence":"additional","affiliation":[{"name":"Department of Oncology New York University Grossman Long Island School of Medicine  Long Island New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Widmer","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology New York University Grossman Long Island School of Medicine  Long Island New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Allendorf","sequence":"additional","affiliation":[{"name":"Department of Surgery New York University Grossman Long Island School of Medicine  Long Island New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao\u2010Zhong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Data Science Tulane University School of Public Health and Tropical Medicine  New Orleans Louisiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,13]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21871"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(25)00261-2"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2019.01.259"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-020-09953-z"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2022.03.056"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/SLA.0000000000004147"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.02233"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9041129"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abb3631"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2023-330480"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djaa216"},{"key":"e_1_2_13_13_1","first-page":"733","article-title":"Stroma 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