2. Academic Validation
  3. Cancer-associated fibroblasts secreting IL-6 inhibit the cisplatin and docetaxel killing effect in lung squamous cell carcinoma

Cancer-associated fibroblasts secreting IL-6 inhibit the cisplatin and docetaxel killing effect in lung squamous cell carcinoma

  • Biochim Biophys Acta Mol Cell Res. 2025 Jul 31;1872(8):120029. doi: 10.1016/j.bbamcr.2025.120029.
Xu Zhu 1,  Long Li 1,  Xuanyin Wang 2,  Ying Zhang 3,  Zeyang Yang 2,  Jiaming Ren 4,  Lu Wang 2,  Xianling Zeng 2,  Jing Xiao 2,  Siyu Wang 2,  Peiying Pan 5,  Jian Zhang 6,  Xiaojun Du 6,  Tao Wang 6,  Langbo Liu 6,  Xiaolin Shu 7,  Qiaoling Zhang 2,  Jiangwei Wu 2,  Siyuan Yang 8,  Xinlei Liu 9,  Zhu Zeng 10,  Jieheng Wu 11
Affiliations

Affiliations

  • 1 Department of Surgery, School of Clinical Medicine, Guizhou Medical University, Guiyang 561113, China; Department of Immunology, Guizhou Medical University, Guiyang 561113, China; Department of Thoracic Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang 550001, China.
  • 2 Department of Immunology, Guizhou Medical University, Guiyang 561113, China.
  • 3 Department of Immunology, Guizhou Medical University, Guiyang 561113, China; Department of Pathology, The Affiliated Hospital of Guizhou Medical University, Guiyang 550001, China; Department of Pathology, Guiyang Maternal and Child Health Care Hospital (Guiyang Children's Hospital), Guiyang 550001, China.
  • 4 Department of Immunology, Guizhou Medical University, Guiyang 561113, China; School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 561113, China.
  • 5 Department of Pathology, The Affiliated Hospital of Guizhou Medical University, Guiyang 550001, China.
  • 6 Department of Surgery, School of Clinical Medicine, Guizhou Medical University, Guiyang 561113, China; Department of Thoracic Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang 550001, China.
  • 7 Department of Orthopedics, The Affiliated Hospital of Guizhou Medical University, Guiyang 550001, China; Department of Orthopedics, Affiliated Hengyang Hospital, Hunan Normal University (Hengyang Central Hospital), Hengyang 421001, China.
  • 8 Department of Surgery, School of Clinical Medicine, Guizhou Medical University, Guiyang 561113, China; Department of Cardiac Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang 550001, China. Electronic address: 15772955@qq.com.
  • 9 Guizhou Prenatal Diagnosis Center, The Affiliated Hospital of Guizhou Medical University, Guiyang 550001, China. Electronic address: 522913224@qq.com.
  • 10 Department of Immunology, Guizhou Medical University, Guiyang 561113, China; Guizhou Key Laboratory of Microbio and Infectious Disease Prevention & Control, School of Basic Medical Sciences, Guizhou Medical University, Guiyang 561113, China. Electronic address: zengzhu@gmc.edu.cn.
  • 11 Department of Immunology, Guizhou Medical University, Guiyang 561113, China; Guizhou Key Laboratory of Microbio and Infectious Disease Prevention & Control, School of Basic Medical Sciences, Guizhou Medical University, Guiyang 561113, China; Tumor Immunotherapy Technology Engineering Research Center of Guizhou Medical University, Guizhou Medical University, Guiyang 561113, China. Electronic address: wujiehen@gmc.edu.cn.
PMID: 40752594 DOI: 10.1016/j.bbamcr.2025.120029
Abstract

Chemoresistance remains a major obstacle in the treatment of lung squamous cell carcinoma (LUSC), often leading to suboptimal clinical outcomes. Among the key contributors to this resistance are cancer-associated fibroblasts (CAFs), which are increasingly recognized for their tumor-supportive roles. Despite this, the molecular pathways through which CAFs promote chemoresistance in LUSC are not fully elucidated. This study found that CAFs-derived interleukin-6 (IL-6) upregulated the expression of Specificity Protein 1 (SP1) and the ATP-binding cassette transporter B7 (ABCB7) in LUSC cells exposed to cisplatin and docetaxel. In vitro assays showed a marked decrease in Apoptosis in tumor cells co-cultured with CAFs. Consistent with these findings, in vivo xenograft models demonstrated that IL-6-producing CAFs reduced the antitumor efficacy of both chemotherapeutic agents. Elevated serum IL-6 levels also emerged as a potential indicator of poor response to chemotherapy. Our findings suggest that IL-6 secreted by CAFs impairs the cytotoxic effects of cisplatin and docetaxel in LUSC, partly through activation of the PI3K/Akt/NF-κB signaling axis. Targeting this IL-6-mediated pathway may offer a promising strategy to overcome chemoresistance and enhance therapeutic outcomes in patients with LUSC.

Keywords

Cancer-associated fibroblasts; Chemotherapy; IL-6; Lung squamous cell carcinoma; Tumor microenvironment.

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