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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy with poor response to standard therapies. While Dabrafenib plus Trametinib (DT) combination therapy has improved the survival of patients with BRAF-mutant ATC, resistance remains a challenge. Given the association of macrophages with poor prognosis, and that SPRY4 has emerged as a mediator in ATC\u2013macrophage interactions, we investigated their role in DT resistance and evaluated the therapeutic potential of macrophage targeting. Transwell co-cultures of BRAF-mutant ATC cell lines (T235 and T238) with THP-1-derived macrophages were established, and viability, invasion, and macrophage phenotype were assessed. Macrophages were also characterised in tumour samples from eleven ATC patients treated with DT. In vitro, DT significantly reduced ATC cell viability and invasion. However, macrophage co-culture significantly restored these effects, also promoting cytoskeletal remodelling and increased vimentin expression, despite DT treatment. DT significantly downregulated SPRY4 and suppressed MAPK signalling and PD-L1. These effects were also significantly reversed by macrophages. Under DT, macrophages showed an increase in M2-like polarisation in co-culture. Patients\u2019 tumour samples were highly infiltrated with macrophages. In vitro targeting of macrophages with Edicotinib, in combination with DT, significantly enhanced the anti-tumour effects of DT and decreased the M2-like polarisation, bypassing the macrophage-mediated DT resistance. Overall, the in vitro findings suggest that macrophages modulate ATC response to DT by enhancing viability, invasion, MAPK signalling and PD-L1, supporting a pro-tumoural phenotype. Targeting macrophages overcomes this resistance, highlighting the CSF1\/CSF1R signalling pathway within the ATC\u2013macrophage axis as a promising therapeutic target to improve DT efficacy.<\/jats:p>","DOI":"10.3390\/ijms27177691","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T16:47:13Z","timestamp":1787849233000},"page":"7691","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Macrophages as Drivers of Resistance to Dabrafenib Plus Trametinib Therapy in Anaplastic Thyroid Cancer"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1928-4106","authenticated-orcid":false,"given":"Ricardo","family":"Rodrigues","sequence":"first","affiliation":[{"name":"Unidade de Investiga\u00e7\u00e3o em Patobiologia Molecular (UIPM), Instituto Portugu\u00eas de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Professor Lima Basto, 1099-023 Lisboa, Portugal"},{"name":"Faculdade de Ci\u00eancias M\u00e9dicas, Universidade NOVA de Lisboa, Campo dos M\u00e1rtires da P\u00e1tria, 130, 1169-056 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7771-5331","authenticated-orcid":false,"given":"Beatriz","family":"Garcia","sequence":"additional","affiliation":[{"name":"Unidade de Investiga\u00e7\u00e3o em Patobiologia Molecular (UIPM), Instituto Portugu\u00eas de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Professor Lima Basto, 1099-023 Lisboa, Portugal"},{"name":"Faculdade de Ci\u00eancias e Tecnologia, Universidade NOVA de Lisboa, Campus da Caparica, 2829-516 Caparica, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0226-5905","authenticated-orcid":false,"given":"Miguel","family":"Rito","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Anatomia Patol\u00f3gica, Instituto Portugu\u00eas de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Professor Lima Basto, 1099-023 Lisboa, Portugal"},{"name":"Instituto de Anatomia Patol\u00f3gica, Faculdade de Medicina da Universidade de Lisboa, Av. 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