Tribbles Pseudokinase 3 Converts Sorafenib Therapy to Neutrophil‐Mediated Lung Metastasis in Hepatocellular Carcinoma

Rapid development of resistance to sorafenib and subsequent hyperprogression in patients with advanced hepatocellular carcinoma (HCC) pose significant challenges, with the underlying mechanisms still largely unknown. Herein, sorafenib-induced TRIB3 is identified as a liver-specific determinant driving secondary resistance to sorafenib by facilitating the accumulation of protumorigenic neutrophils within tumors. Mechanistically, TRIB3, triggered by the sorafenib-elicited ROS-ER stress axis, operates in an NF-κB-dependent manner to upregulate CXCR1/2 ligands, subsequently promoting neutrophil recruitment into tumors. These enriched neutrophils enhance epithelial-mesenchymal transition processes in malignant cells through the oncostatin M-STAT3 pathway, thereby repurposing the therapeutic efficacy of sorafenib away from anti-angiogenesis 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-induced hyperprogression in vivo. The study thus identifies a pivotal mechanism of sorafenib resistance in HCC, centered on the TRIB3-mediated recruitment of protumorigenic neutrophils and subsequent disease hyperprogression.