{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T16:30:42Z","timestamp":1772987442799,"version":"3.50.1"},"reference-count":27,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T00:00:00Z","timestamp":1766966400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T00:00:00Z","timestamp":1766966400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003696","name":"Electronics and Telecommunications Research Institute","doi-asserted-by":"publisher","award":["24YK1110"],"award-info":[{"award-number":["24YK1110"]}],"id":[{"id":"10.13039\/501100003696","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004332","name":"Seoul National University Hospital","doi-asserted-by":"publisher","award":["2620210050"],"award-info":[{"award-number":["2620210050"]}],"id":[{"id":"10.13039\/501100004332","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2020M3A9B6037195"],"award-info":[{"award-number":["2020M3A9B6037195"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS\u20102024\u201000357094"],"award-info":[{"award-number":["RS\u20102024\u201000357094"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Hypopharyngeal squamous cell carcinoma (SCC) is an aggressive malignancy with a poor prognosis, particularly in advanced stages. Concurrent chemoradiotherapy (CCRT) is frequently employed to preserve the larynx, but resistance to CCRT remains a significant clinical challenge. Understanding the tumor microenvironment (TME) in CCRT\u2010resistant cases is crucial for identifying predictive biomarkers and developing targeted therapies to improve outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study analyzed tissue samples from patients with advanced hypopharyngeal SCC who were either resistant to CCRT or had not received CCRT. Spatial transcriptomics (ST) was used to explore the spatial molecular signatures within the TME of these samples, focusing on the interactions between immune cells and malignant cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified six distinct cellular clusters in the hypopharyngeal SCC tissues, with a signature cluster more prominently present in CCRT\u2010resistant samples. The SPP1 gene was significantly overexpressed in these samples, specifically in macrophages, and was associated with increased ligand\u2013receptor interactions involving malignant cells via CD44 and ITGB1. These interactions were primarily observed in peri\u2010tumoral and intratumoral regions, indicating a role for SPP1+ macrophages in modulating the TME and contributing to CCRT resistance. Further analysis revealed that SPP1\u2010mediated cell\u2013cell interactions predominantly occurred between macrophages and malignant epithelial cells, highlighting their potential role in driving therapeutic resistance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings suggest that SPP1\u2010expressing macrophages play a pivotal role in the development of CCRT resistance in hypopharyngeal SCC through specific interactions with malignant cells. The spatial distribution of these macrophages and their interaction with cancer cells suggest a mechanism by which the TME contributes to therapeutic failure. These insights could inform the development of novel targeted therapies aimed at overcoming CCRT resistance, ultimately improving patient outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cam4.71493","type":"journal-article","created":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T06:53:37Z","timestamp":1767077617000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spatial Transcriptomics Unveils Landscape of Resistance to Concurrent Chemo\u2010Radiotherapy in Hypopharyngeal Squamous Cell Carcinoma: The Role of\n                    <scp>\n                      <i>SPP1<\/i>\n                    <\/scp>\n                    <sup>\n                      <i>+<\/i>\n                    <\/sup>\n                    Macrophages"],"prefix":"10.1002","volume":"15","author":[{"given":"Jungyoon","family":"Ohn","sequence":"first","affiliation":[{"name":"Portrai, Inc.  Seoul Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sungwoo","family":"Bae","sequence":"additional","affiliation":[{"name":"Portrai, Inc.  Seoul Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8895-2449","authenticated-orcid":false,"given":"Hongyoon","family":"Choi","sequence":"additional","affiliation":[{"name":"Portrai, Inc.  Seoul Republic of Korea"},{"name":"Department of Nuclear Medicine Seoul National University Hospital  Seoul Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiwon","family":"Koh","sequence":"additional","affiliation":[{"name":"Department of Pathology Seoul National University Hospital  Seoul Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"In Gul","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery, Biomedical Research Institute Seoul National University Hospital  Seoul Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eun\u2010Jae","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery, Biomedical Research Institute Seoul National University Hospital  Seoul Republic of Korea"},{"name":"Department of Otolaryngology\u2010Head and Neck Surgery Seoul National University College of Medicine  Seoul Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4158-9790","authenticated-orcid":false,"given":"Kwon Joong","family":"Na","sequence":"additional","affiliation":[{"name":"Portrai, Inc.  Seoul Republic of Korea"},{"name":"Department of Thoracic and Cardiovascular Surgery Seoul National University Hospital  Seoul Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,12,29]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm13133853"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/hed.21613"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2018.12.015"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3958"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci13040542"},{"key":"e_1_2_13_7_1","first-page":"255","volume-title":"Cancer Immunology and Genetics: An Interdisciplinary Approach","author":"Ibarra L. 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