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

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.