CAF-Secreted Exosomes Deliver BMP4 to Confer Radiotherapy Resistance in Cervical Cancer Through a Novel Mechanism Linking Nrf2 Activation to Cuproptosis Inhibition.
Chi Chi, Xu Mindan, Zhang Jie, Zhang Yi, Han Guorong, Li Min
Abstract
This study elucidates a novel intercellular communication mechanism underlying radiotherapy resistance in cervical cancer, focusing on the functional role of cancer-associated fibroblast-derived exosomes (CAF-Exo) in modulating redox homeostasis and cell death pathways. We demonstrate that CAF-Exo serve as critical vehicles for transferring radioresistant phenotypes to tumor cells through coordinated regulation of antioxidant defense systems and copper-dependent cell death processes. Our findings reveal that CAF-Exo activate the Nrf2-HO-1 signaling axis while simultaneously suppressing key cuproptosis regulators, establishing a dual-pathway mechanism for treatment resistance. Bone morphogenetic protein 4 (BMP4) was identified as the essential molecular cargo within these exosomes, functioning as a master regulator of this protective cellular response. The pathological significance of this pathway was confirmed through comprehensive functional assays showing that BMP4 knockdown effectively restored radiosensitivity in vitro and significantly enhanced radiotherapy efficacy in vivo. These results uncover a previously unrecognized biological axis wherein tumor-stroma interactions mediated by exosomal BMP4 orchestrate a sophisticated defense mechanism against radiotherapy-induced stress. This study elucidates key molecular mechanisms underlying treatment resistance and highlights potential therapeutic targets for cervical cancer, offering a basis for future intervention strategies.
Key Findings
- CAF-derived exosomes deliver BMP4 to cervical cancer cells, activating the Nrf2-HO-1 antioxidant signaling pathway.
- Activation of Nrf2 by exosomal BMP4 concurrently suppresses cuproptosis regulators, contributing to radiotherapy resistance.
- Knockdown of BMP4 restores radiosensitivity in vitro and enhances radiotherapy efficacy in vivo, confirming its role in treatment resistance.
Clinical Significance
Targeting the BMP4-mediated activation of Nrf2 and inhibition of cuproptosis presents a promising therapeutic strategy to overcome radiotherapy resistance in cervical cancer patients.
Citation
Chi Chi, Xu Mindan, Zhang Jieet al.. CAF-Secreted Exosomes Deliver BMP4 to Confer Radiotherapy Resistance in Cervical Cancer Through a Novel Mechanism Linking Nrf2 Activation to Cuproptosis Inhibition. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2026-May-15.