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.
- 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: [email protected].
- 9. Guizhou Prenatal Diagnosis Center, The Affiliated Hospital of Guizhou Medical University, Guiyang 550001, China. Electronic address: [email protected].
- 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: [email protected].
- 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: [email protected].
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.