{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:31:03Z","timestamp":1787027463931,"version":"build-2736575974"},"reference-count":111,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,16]],"date-time":"2026-08-16T00:00:00Z","timestamp":1786838400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Follicular-cell-derived thyroid cancers that progress from differentiated tumors to poorly differentiated or anaplastic states commonly lose thyroid lineage identity, radioiodine avidity, and favorable clinical behavior. Genetic and signaling alterations within tumor cells explain part of this transition, but they do not fully account for the coexistence of different differentiation states within the same molecular subtype or even within the same lesion. Increasing functional evidence indicates that dedifferentiation is maintained by reciprocal interactions between malignant cells and the immune, stromal, metabolic, and inflammatory microenvironment. Cancer-associated fibroblast glycolysis and lactate release, IL-6\/CXCL8-driven inflammatory signaling, hypoxia, transforming growth factor-beta signaling, and tumor-associated macrophage feedback can suppress thyroid lineage programs while promoting plasticity, invasion, and treatment resistance. Here, we synthesize mechanistic studies supported by genetic perturbation, co-culture, pharmacologic blockade, iodine-uptake assays, animal models, or patient-level radioiodine endpoints. We distinguish functional dedifferentiation from epithelial\u2013mesenchymal transition, stemness, and lymph-node metastasis, and discuss therapeutic strategies that combine tumor-cell redifferentiation with targeting of microenvironmental feedback to restore durable radioiodine sensitivity.<\/jats:p>","DOI":"10.3390\/ijms27167305","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:01:26Z","timestamp":1786968086000},"page":"7305","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Microenvironmental Control of Thyroid Cancer Plasticity and Radioiodine Resistance"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-4475-6317","authenticated-orcid":false,"given":"Qing","family":"Ye","sequence":"first","affiliation":[{"name":"Zhejiang Provincial Key Laboratory of Biometrology and Inspection and Quarantine, College of Life Science, China Jiliang University, Hangzhou 310018, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Ping","family":"Yu","sequence":"additional","affiliation":[{"name":"Zhejiang Provincial Key Laboratory of Biometrology and Inspection and Quarantine, College of Life Science, China Jiliang University, Hangzhou 310018, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1056\/NEJMra1501993","article-title":"Biologic and Clinical Perspectives on Thyroid Cancer","volume":"375","author":"Fagin","year":"2016","journal-title":"N. 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