CXCL6 Reshapes Lipid Metabolism and Induces Neutrophil Extracellular Trap Formation in Cholangiocarcinoma Progression and Immunotherapy Resistance

CXCL6 Reshapes Lipid Metabolism and Induces Neutrophil Extracellular Trap Formation in Cholangiocarcinoma Progression and Immunotherapy Resistance

Abstract The chemokine CXCL6 is identified as a pivotal regulator of biological processes across multiple malignancies. However, its function in cholangiocarcinoma (CCA) is underexplored. Tumor profiling for CXCL6 is performed using a public database. Both in vitro and in vivo experiments are utiliz...

Full description

Saved in:
Bibliographic Details
Main Authors: Tian He, Zi‐Yi Wang, Bin Xu, Cheng‐Jie Zhong, Lu‐Na Wang, Huan‐Chen Shi, Zi‐Yue Yang, Shi‐Qi Zhou, Hui Li, Bo Hu, Xiao‐Dong Zhu, Ying‐Hao Shen, Jian Zhou, Jia Fan, Hui‐Chuan Sun, Cheng Huang
Format: Article
Language:English
Published: Wiley 2025-07-01
Series:Advanced Science
Subjects:
Cholangiocarcinoma
CXCL6
Lipid metabolism
Neutrophil extracellular traps
Immunotherapy
Online Access:https://doi.org/10.1002/advs.202503009
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Abstract The chemokine CXCL6 is identified as a pivotal regulator of biological processes across multiple malignancies. However, its function in cholangiocarcinoma (CCA) is underexplored. Tumor profiling for CXCL6 is performed using a public database. Both in vitro and in vivo experiments are utilized to evaluate the oncogenic effects of CXCL6 on CCA. Additionally, RNA‐Seq is employed to detect transcriptomic changes related to CXCL6 expression in CCA cells and neutrophils. Molecular docking, fluorescence colocalization, and Co‐IP are used to elucidate a direct interaction between JAKs and CXCR1/2. Additionally, LC‐MS lipidomics and explored the impact of CXCL6 on immunotherapy in vivo. CXCL6 is upregulated in CCA tissues and promoted the proliferation and metastasis of CCA. Mechanistically, CXCL6 regulated the CXCR1/2‐JAK‐STAT/PI3K axis in CCA via autocrine signaling, leading to lipid metabolic reprogramming, and promoted neutrophil extracellular traps (NETs) formation by activating the RAS/MAPK pathway in neutrophils. Eventually, NETs formation induced immunotherapy resistance in CCA by blocking CD8+T cell infiltration. CXCL6 modulates CCA progression through the CXCR1/2‐JAK‐STAT/PI3K axis and reshaping its lipid metabolism. CXCL6 also mediates immunotherapy resistance through NETs, which may be a potential therapeutic target and biomarker for CCA.
ISSN:2198-3844

Similar Items