{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T16:18:19Z","timestamp":1787847499550,"version":"build-2784847793"},"reference-count":47,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82203704"],"award-info":[{"award-number":["82203704"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82373449"],"award-info":[{"award-number":["82373449"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>Tumors actively remodel the tumor microenvironment (TME) to foster therapy resistance. However, the underlying mechanisms remain poorly defined. This study aims to characterize how colorectal cancer (CRC) cells drive TME remodeling to promote radioresistance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A radioresistant CRC cell line was established via serial in vivo irradiation. Single\u2010cell RNA sequencing characterized TME alterations. The role of tumor\u2010derived small extracellular vesicles (sEVs) in macrophage polarization was assessed. Proteomic analysis identified ANXA2 as a key sEVs cargo, and calcium\u2010dependent sEV secretion was investigated through SLC8A1 modulation. Clinical relevance analyses were further assessed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The radioresistant model exhibited enhanced treatment resistance to irradiation and increased infiltration of M2\u2010like tumor\u2010associated macrophages (TAMs), while TAM depletion restored radiosensitivity. Tumor\u2010derived sEVs promoted M2 polarization by activating STAT6 phosphorylation, with ANXA2 as the key functional cargo. Further analysis revealed that SLC8A1 deficiency increased intracellular Ca\n                      <jats:sup>2<\/jats:sup>\n                      <jats:sup>+<\/jats:sup>\n                      levels, boosting secretion of ANXA2\n                      <jats:sup>+<\/jats:sup>\n                      sEVs and subsequent TAM M2 polarization. Clinically, low SLC8A1 expression correlated with higher M2 TAM infiltration, poorer therapeutic response, and worse survival outcomes in CRC patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      CRC cells with low SLC8A1 expression remodel the TME to foster radioresistance via calcium\u2010dependent secretion of ANXA2\n                      <jats:sup>+<\/jats:sup>\n                      sEVs and subsequent M2 polarization of TAMs.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/advs.77308","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T15:20:02Z","timestamp":1787844002000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Low SLC8A1 in Colorectal Cancer Dictates Radiotherapy Resistance Through Calcium\u2010Dependent ANXA2\n                    <sup>+<\/sup>\n                    sEVs Driving M2 Polarization of TAMs"],"prefix":"10.1002","author":[{"given":"Yimin","family":"Fang","sequence":"first","affiliation":[{"name":"Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention China National Ministry of Education) The Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou Zhejiang China"},{"name":"Center for Medical Research and Innovation in Digestive System Tumors Ministry of Education  Hangzhou Zhejiang China"},{"name":"Zhejiang Provincial Clinical Research Center for Cancer  Hangzhou Zhejiang China"},{"name":"Cancer Center of Zhejiang University  Hangzhou Zhejiang China"},{"name":"Department\u00a0of\u00a0Gynecology The Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou Zhejiang 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