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Herein, sorafenib\u2010induced TRIB3 is identified as a liver\u2010specific determinant driving secondary resistance to sorafenib by facilitating the accumulation of protumorigenic neutrophils within tumors. Mechanistically, TRIB3, triggered by the sorafenib\u2010elicited ROS\u2010ER stress axis, operates in an NF\u2010\u03baB\u2010dependent manner to upregulate CXCR1\/2 ligands, subsequently promoting neutrophil recruitment into tumors. These enriched neutrophils enhance epithelial\u2010mesenchymal transition processes in malignant cells through the oncostatin M\u2010STAT3 pathway, thereby repurposing the therapeutic efficacy of sorafenib away from anti\u2010angiogenesis and toward lung metastasis. Clinically, elevated TRIB3 expression indicates inferior survival and unfavorable clinical efficacy of sorafenib in HCC patients. Correspondingly, strategies that either inhibiting TRIB3 upregulation or blocking its downstream signaling successfully augment the therapeutic efficacy of sorafenib and prevent sorafenib\u2010induced hyperprogression in vivo. The study thus identifies a pivotal mechanism of sorafenib resistance in HCC, centered on the TRIB3\u2010mediated recruitment of protumorigenic neutrophils and subsequent disease hyperprogression.<\/jats:p>","DOI":"10.1002\/advs.202413682","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T11:02:48Z","timestamp":1739271768000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Tribbles Pseudokinase 3 Converts Sorafenib Therapy to Neutrophil\u2010Mediated Lung Metastasis in Hepatocellular Carcinoma"],"prefix":"10.1002","volume":"12","author":[{"given":"Xu\u2010Yan","family":"Wang","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Liver Disease Research The Third Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou 510630 China"},{"name":"State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer 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