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This study investigated whether ultrasound\u2010targeted microbubble destruction (UTMD), a non\u2010invasive physical modality, could reprogram the TME through modulation of TAMs and induction of ferroptosis. Transcriptomic profiling identified CSF\u20101 as a top target suppressed by UTMD, which was validated by ELISA, Western blot, and qRT\u2010PCR. UTMD time\u2010dependently inhibited CSF\u20101 expression and secretion, consequently attenuating PTC\u2010induced M2 macrophage polarization as evidenced by decreased CD206\n                    <jats:sup>+<\/jats:sup>\n                    cells and M2 marker expression. Exogenous CSF\u20101 rescued this effect, confirming the specificity of the mechanism. Functionally, M1 macrophages selectively induced ferroptotic death in PTC cells, whereas M2 macrophages promoted viability and ferroptosis resistance via GPX4 upregulation and suppression of lipid peroxidation. Critically, UTMD overcame M2\u2010mediated protection by downregulating CSF\u20101, thereby sensitizing PTC cells to ferroptosis both in\u00a0vitro and in\u00a0vivo. In a subcutaneous xenograft model, UTMD significantly inhibited tumor growth, reduced intratumoral CSF\u20101 and M2\u2010TAMs, increased M1\u2010TAMs, and triggered ferroptosis hallmarks including mitochondrial shrinkage and GPX4 downregulation. These findings establish that UTMD suppresses PTC\u2010derived CSF\u20101 to drive TAM repolarization from M2 to M1, consequently sensitizing tumor cells to ferroptosis. This dual reprogramming of immune and metabolic TMEs positions UTMD as a promising non\u2010pharmacological strategy for refractory PTC.\n                  <\/jats:p>","DOI":"10.1002\/cam4.72220","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T07:48:48Z","timestamp":1787816928000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>UTMD<\/scp>\n                    Suppresses\n                    <scp>CSF<\/scp>\n                    \u20101 to Drive Macrophage\u2010Mediated Ferroptosis in Papillary Thyroid Carcinoma"],"prefix":"10.1002","volume":"15","author":[{"given":"Yanqiang","family":"Niu","sequence":"first","affiliation":[{"name":"Department of Ultrasound Medicine Gansu Provincial Hospital  Lanzhou Gansu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenqiang","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Ultrasound Medicine Gansu Provincial Hospital  Lanzhou Gansu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ultrasound Medicine Gansu Provincial Hospital  Lanzhou Gansu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayan","family":"Zhang","sequence":"additional","affiliation":[{"name":"First Clinical Medical College Gansu University of Chinese Medicine  Lanzhou Gansu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yushan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Ultrasound Medicine Gansu Provincial Hospital  Lanzhou Gansu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhui","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Ultrasound Medicine Gansu Provincial Hospital  Lanzhou Gansu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0682-9552","authenticated-orcid":false,"given":"Zubang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Ultrasound Medicine Gansu Provincial Hospital  Lanzhou Gansu China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"e_1_2_13_2_1","volume-title":"IARC World Cancer Reports","author":"Wild C. 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