Small Extracellular Vesicles‐Derived Circ6718 Unlocks Stromal Remodeling and Serves as a Biomarker in Gastric Cancer

ABSTRACT Small extracellular vesicles (sEVs)‐derived circular RNA (circRNA) serves as a crucial biomarker for diagnosing gastric cancer and as a key regulator of tumor progression, orchestrating intercellular crosstalk within the tumor microenvironment (TME). In gastric cancer (GC), tissue‐derived mesenchymal stem cells (GC‐MSCs) critically drive tumor progression; however, the interplay between sEVs and circRNA in GC‐MSCs remains incompletely understood. We identified sEVs‐hsa_circ_0006718 (circ6718) as significantly upregulated in gastric cancer patients. Elevated levels of sEVs‐circ6718 correlated with clinical stage, distant metastasis and poor prognosis, confirming its utility as both an early diagnostic and prognostic biomarker in GC. Mechanistically, circ6718 functions as a competing endogenous RNA (ceRNA) by sequestering hsa‐miR‐561‐3p, thereby derepressing the expression of SAAL1 (Serum amyloid A‐like 1). SAAL1 enhances the transcriptional activity of PRRX1 (Paired related homeobox 1), which directly activates the TGFβ1 promoter. Consequently, the TGFβ1/Smad2/3 signaling pathway drives the transdifferentiation of GC‐MSCs into cancer‐associated fibroblasts (CAFs)—promoting stromal remodeling and tumor aggressiveness. Our findings unveil a novel sEVs‐circRNA‐mediated axis in GC progression, revealing dual utility in diagnostics and targeted therapy.