ARID1A deficiency reprograms the tumor secretome, enhancing microenvironmental remodeling and metastatic dissemination in endometrial carcinoma.

Loss-of-function mutations in AT-rich interactive domain-containing protein 1 A (ARID1A), accompanied by reduced protein expression, are common in endometrial carcinoma (EC) and correlate with shorter progression-free survival. Alterations in the EC cells secretome play a critical role in shaping the tumor microenvironment (TME), thereby promoting disease progression, metastasis, and therapeutic resistance. Here, we demonstrate that ARID1A-deficient EC cells display a reprogrammed soluble secretome that alters tumor-stromal communication. Among the secreted factors, CXCL16 emerges as the predominant chemokine, promoting epithelial-to-mesenchymal transition and enhancing tumor cell invasiveness. Mechanistically, CXCL16 activates MAPK and Paxillin/FAK pathways, driving YAP/TAZ signaling and reinforcing pro-tumorigenic features. Elevated CXCL16 levels within the tumor niche also promote the conversion of stromal cells into cancer-associated fibroblasts (CAFs) in both preclinical models and patient samples of ARID1A-deficient EC. Importantly, genetic or pharmacological inhibition of CXCL16 or its receptor CXCR6 disrupts these pathogenic interactions, impairing EC cell migration and reducing metastatic burden. These findings identify the secretome of ARID1A-deficient EC cells as a key driver of tumor progression and underscore the CXCL16-CXCR6 axis as a promising therapeutic target in EC.