COL11A1-packaged extracellular vesicles from THY1+ cancer-associated fibroblasts confer oxaliplatin resistance and unfavorable prognosis in gastric cancer.

Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment and play important roles in cancer progression and treatment resistance. Despite recognized heterogeneity among CAFs, their specific contributions to chemoresistance in gastric cancer (GC) remain incompletely understood. This study identifies THY1+ CAFs as a distinct subset associated with poor patient outcomes and oxaliplatin resistance in GC. Both in vitro and in vivo analyses confirmed that THY1+ CAFs promote oxaliplatin resistance in GC cells via extracellular vesicles (EVs). Inhibition of EV secretion reduced the chemoresistance-enhancing effects of THY1+ CAFs. Proteomic profiling of EVs identified COL11A1 as a protein enriched in THY1+ CAF-derived EVs, which was further validated by immunofluorescence and Western blot. Depletion of COL11A1 in THY1+ CAF-EVs substantially attenuated their ability to enhance drug resistance in GC cells. High infiltration of COL11A1+ and THY1+ CAFs was correlated with reduced overall survival and recurrence-free survival in GC patients. RNA sequencing and pathway analysis revealed that THY1+ CAF-EVs induce oxaliplatin resistance by activating the PI3K/AKT signaling pathway. Targeting PI3K/AKT signaling counteracted EV-induced chemoresistance, and COL11A1 knockdown in THY1+ CAF-EVs reduced PI3K/AKT activation. In conclusion, COL11A1 packaged in THY1+ CAF-derived EVs promotes GC chemoresistance via PI3K/AKT signaling, highlighting a potential therapeutic target for overcoming chemoresistance in GC.