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Lipid metabolism reprogramming, TGF\u03b2 signaling, and cancer-associated fibroblast (CAF) activation have each been linked to cetuximab resistance, but how these processes mechanistically converge remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We integrated transcriptomic, metabolic, and biochemical assays in HNSCC cell lines, co-culture systems with matched patient-derived non tumoral fibroblasts and CAFs, patient-derived organoids (PDOs), and patient-derived xenografts (PDXs) to characterize tumor-stroma interactions during cetuximab treatment. Fluorescence-based fatty acid (FA) tracing and lipidomic analyses were used to assess FA flux. Functional relevance was tested through genetic and pharmacologic inhibition of TGF-\u03b22 signaling and FA transfer. Clinical relevance was assessed by analyzing\n                      <jats:italic>TGFB2<\/jats:italic>\n                      expression and plasma TGF-\u03b22 levels in HNSCC patient cohorts.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Cetuximab-treated HNSCC cells specifically upregulated and secreted TGF-\u03b22, which induced two coordinated adaptive programs: (i) autocrine metabolic rewiring promoting FA uptake, oxidation, and storage in tumor cells, and (ii) paracrine activation of fibroblasts toward a myofibroblastic, lipid-secreting phenotype. These TGF\u03b22-activated CAFs supplied FA that sustained oxidative metabolism and preserved EGFR\/MAPK signaling in tumor cells, establishing a reciprocal feedback loop that maintained a reversible drug-tolerant state. Disrupting either TGF-\u03b22 signaling or FA transfer abrogated this circuit and restored cetuximab sensitivity in HNSCC cells, spheroids, and PDOs. In PDX models, TGF-\u03b22 inhibition delayed tumor regrowth following cetuximab treatment. Elevated\n                      <jats:italic>TGFB2<\/jats:italic>\n                      expression and circulating TGF-\u03b22 levels were associated with metabolic reprogramming and poorer clinical outcomes following cetuximab therapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings define a tumor-stroma metabolic cooperation axis in which TGF\u03b22-driven lipid exchange sustains adaptive cetuximab tolerance in HNSCC. Targeting TGF\u03b22-mediated stromal reprogramming or FA transfer represents a promising strategy to delay or overcome resistance to EGFR-targeted therapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-026-03765-9","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T08:44:23Z","timestamp":1782290663000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Reciprocal signaling-metabolic crosstalk between fibroblasts and tumor cells drives cetuximab tolerance in head and neck cancers"],"prefix":"10.1186","volume":"45","author":[{"given":"Engy","family":"Vigneron","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Vignau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Lowyck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentin","family":"Van den bossche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9r\u00f4me","family":"Ambroise","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yann","family":"Kieffer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima","family":"Mechta-Grigoriou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Rizzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Virginia","family":"Giolito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manon","family":"Desgres","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Zaryouh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An","family":"Wouters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Mendola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajar","family":"Dahou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marine","family":"Leclerc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romain","family":"Boidot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aur\u00e9lien","family":"Warnant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvan","family":"Larondelle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Feron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pascal","family":"Machiels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Schmitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyril","family":"Corbet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"key":"3765_CR1","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung H, et al. 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All patients provided written informed consent in accordance with the Declaration of Helsinki. In vivo mouse experiments with PDX models were approved by the ethics committee from UCLouvain (approval ID UCL\/MD\/2012\/09July\/314) in accordance with the principles of the Declaration of Helsinki, and all patients gave their written informed consent. Experiments involving mouse xenografts received the approval of the ethics committee from UCLouvain (approval ID 2022\/UCL\/MD\/024 and 2020\/UCL\/MD\/032) and were carried out according to national care regulations.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"193"}}