CLCF1–ZIC5–CNTFR feedback loop drives cisplatin resistance in cervical squamous cell carcinoma

Cervical squamous cell carcinoma (CESC) is frequently complicated by cisplatin (CDDP) resistance, which is a primary cause of treatment failure and poor prognosis. Here, we identified a CLCF1-ZIC5-CNTFR feedback loop that contributes to CDDP resistance in CESC. We found that ZIC5 was significantly upregulated in CDDP-resistant CESC and correlated with worse overall survival. Functionally, ZIC5 promoted CDDP resistance, in part by enhancing properties associated with cancer stem cells (CSCs) through the transcriptional activation of CNTFR. CLCF1, the ligand for CNTFR, was found to induce ZIC5 expression via STAT3 signaling, thereby forming a CLCF1-ZIC5-CNTFR positive feedback loop. Targeting CNTFR with a neutralizing antibody disrupted this regulatory circuit, leading to a reversal of CDDP resistance and suppression of CSC-associated phenotypes in vitro. Furthermore, combining an anti-CNTFR antibody with CDDP resulted in enhanced antitumor effects in patient-derived xenograft (PDX) and organoid (PDO) models. In summary, our findings suggest that the CLCF1-ZIC5-CNTFR positive feedback loop promotes CDDP resistance in CESC, potentially by sustaining CSC properties. Targeting this pathway, particularly CNTFR, may represent a potential therapeutic strategy for patients with CDDP-resistant CESC.