Cancer-associated fibroblast-derived fibulin-5 promotes radioresistance in non-small-cell lung cancer

Radioresistance impedes the effectiveness of cancer radiotherapy, particularly due to the persistence of cancer-associated fibroblasts (CAFs) post-radiation. This study aims to identify CAF-expressed molecules predicting radiotherapy efficacy and to clarify the resistance mechanisms in non-small-cell lung cancer (NSCLC). We identified higher Fibulin-5 (FBLN5) expression in the stromal regions of recurrent patients after radiotherapy utilizing spatial transcriptomics and FBLN5 knockdown in CAFs enhanced radiosensitivity. Mechanistically, Fibulin-5 binds to integrin αVβ5 receptor, activates the Src-STAT3 pathway in CAFs and cancer cells, downregulates acyl-CoA synthetase long-chain family member 4 (ACSL4), and impairs irradiation-activated ferroptosis. Radioresistant cancer cells are more capable of converting normal fibroblasts to CAFs, upregulating FBLN5 via exosomal miRNA. Activated CAFs further promote tumor radioresistance, confirmed by single-cell RNA sequencing. Clinical tissue analysis showed that elevated Fibulin-5 expression is correlated with fibroblast activation and radioresistance. Thus, high Fibulin-5 expression in CAFs serves as a predictive biomarker for radiotherapy efficacy and a potential therapeutic target to improve NSCLC radiosensitivity.