{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T03:29:30Z","timestamp":1786418970648,"version":"build-2736575974"},"reference-count":39,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"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 Medicine"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Colon adenocarcinoma (COAD) is a prevalent gastrointestinal malignancy characterized by dysregulation of multiple cellular signaling pathways, including the Notch pathway. However, the specific biological roles of Notch3 and Notch4 in COAD remain incompletely characterized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We aimed to investigate the effects of Notch3 and Notch4 downregulation on the tumor immune microenvironment and angiogenesis in COAD. Using a combination of in\u00a0vitro and in\u00a0vivo models, we evaluated the impacts of Notch3\/4 interference on cell proliferation, migration, immune cell infiltration, and tumor progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Interfering with Notch3 and 4 significantly suppressed subcutaneous tumor progression. Notably, this inhibition was not only associated with reduced cell viability, but also with an altered immune environment characterized by enhanced macrophage M1 polarization and T lymphocyte activation, which may be linked to the c\u2010Myc\/VEGFA signaling axis but requires further mechanistic validation. Furthermore, the combination of regorafenib and Notch3\/4 knockout (KO) exerted enhanced anti\u2010tumor effects. More importantly, Mol_2, a candidate compound with predicted binding affinity for both Notch3 and Notch4, was screened out to significantly reduce the protein levels of Notch3 and Notch4 and tumor progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings suggest that targeting Notch3 and Notch4 receptors may have therapeutic potential for modulating the tumor microenvironment and suppressing tumor progression in COAD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cam4.72121","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T03:32:59Z","timestamp":1784172779000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Notch3\/4 Knockdown Inhibits Colon Adenocarcinoma Progression by Suppressing Tumor Cell Activity and Orchestrating\n                    <scp>VEGFA<\/scp>\n                    \u2010Dependent Tumor Immune Microenvironment"],"prefix":"10.1002","volume":"15","author":[{"given":"Wei","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Oncology The Affiliated Dazu's Hospital of Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guhang","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Oncology The Affiliated Dazu's Hospital of Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningfu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Oncology The Affiliated Dazu's Hospital of Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiasheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oncology The Affiliated Dazu's Hospital of Chongqing Medical 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