2. Academic Validation
  3. Lenvatinib-resistant liver cancer-derived HSP90α-containing extracellular vesicles enhance drug resistance via macrophage CXCL8 secretion

Lenvatinib-resistant liver cancer-derived HSP90α-containing extracellular vesicles enhance drug resistance via macrophage CXCL8 secretion

  • Immunol Lett. 2026 Apr:278:107122. doi: 10.1016/j.imlet.2025.107122.
Xin-Wei Xu 1,  Yue Zhang 1,  Cheng-Wen Zhao 1,  Han Wu 1,  Meng-Ting Zhang 1,  Yu-Ting Ma 1,  Yang Yu 2,  Lu Zheng 3,  Feng Gu 4,  Yong-Qiang Chen 5
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory, Xuzhou Institute of Medical Science, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, 221009, Jiangsu, China.
  • 2 Department of Medical Oncology, Xuzhou Central Hospital, Xuzhou, 221009, Jiangsu, China.
  • 3 Department of Clinical Laboratory, Xuzhou Institute of Medical Science, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, 221009, Jiangsu, China. Electronic address: [email protected].
  • 4 Department of Clinical Laboratory, Xuzhou Institute of Medical Science, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, 221009, Jiangsu, China. Electronic address: [email protected].
  • 5 Department of Clinical Laboratory, Xuzhou Institute of Medical Science, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, 221009, Jiangsu, China. Electronic address: [email protected].
PMID: 41349809 DOI: 10.1016/j.imlet.2025.107122
Abstract

The acquisition of lenvatinib resistance has a significant detrimental impact on the clinical efficacy of patients with hepatocellular carcinoma (HCC). Extracellular vesicles (EVs), which act as key mediators of intercellular communication, are implicated in tumor progression and immune evasion. The aim of this research was to investigate whether EVs derived from lenvatinib-resistant HCC cells regulate tumor-associated macrophages and contribute to drug resistance in HCC. The results showed that lenvatinib-resistant HCC cell-derived EVs could upregulate the ERK pathway in macrophages, leading to the secretion of C-X-C motif chemokine ligand 8 (CXCL8), which, in turn, promoted HCC cells resistant to lenvatinib. Mechanistically, lenvatinib-resistant HCC cell-derived EVs regulate the Toll Like Receptor 2 (TLR2)-ERK pathway in macrophages through heat shock protein 90 alpha (HSP90α), thereby promoting the secretion of CXCL8, and activating STAT3 phosphorylation, which in turn upregulates the expression of Programmed Cell Death Ligand 1 (PD-L1). Subsequently, elevated levels of CXCL8 stimulated the CXCL8 receptor CXC Chemokine Receptor 1/2 (CXCR1/2) in HCC cells, inhibited lenvatinib-induced Apoptosis, and increased the expression of P-glycoprotein (P-gp) and Vimentin, thereby promoting epithelial-mesenchymal transition (EMT) and drug resistance in liver Cancer. Conversely, the inhibition of CXCR1/2 abolished its inhibitory effect on lenvatinib-induced Apoptosis, and resulted in the downregulation of P-gp and Vimentin. In conclusion, our study demonstrated that EVs containing HSP90α, derived from lenvatinib-resistant liver Cancer cells, can promote EMT and drug resistance in HCC cells by stimulating CXCL8 secretion from macrophages. This finding may provide new insights and strategies to overcome lenvatinib resistance in the future.

Keywords

CXCL8; Extracellular vesicles; Hepatocellular carcinoma; Lenvatinib; Macrophage; Resistance.

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