Senescent endothelial cell-derived extracellular vesicles promote neoadjuvant chemoresistance in colorectal cancer via GPX4.

Chemotherapy resistance remains a major challenge in advanced colorectal cancer (CRC), with chemotherapy-induced senescence playing a key role. While cancer cell senescence has been extensively studied, the contribution of stromal components, particularly vascular endothelial cells, remains unclear. Here, we analyze 77 CRC patients undergoing neoadjuvant chemotherapy and find that favorable responders exhibit well-defined vascular lumens, whereas poor responders show an increase in senescent endothelial cells (senEndo), as revealed by single-cell transcriptomics and immunofluorescence. Chemotherapy-induced senescence reduces GPX4 ubiquitylation in senEndo, leading to its accumulation and extracellular vesicle transfer to CRC cells, where it inhibits ferroptosis and promotes chemoresistance. In vitro and in vivo models demonstrate that targeting GPX4 with the ferroptosis activator RSL3 restores chemotherapy sensitivity. These findings identify a novel mechanism of chemoresistance mediated by senEndo-derived GPX4 in extracellular vesicles and highlight the potential of ferroptosis induction, alone or in combination with senolytic agents, to improve 5-Fu/oxaliplatin-based CRC therapies.