Exosomal S100A9 promotes lung metastasis of adenoid cystic carcinoma via activating cancer-associated fibroblasts.

Adenoid cystic carcinoma (ACC) is a malignant epithelial neoplasm that arises in secretory glands and commonly metastasizes to the lungs, remaining the primary cause of patient mortality. Here, we observed that S100A9, a calcium-binding protein, was significantly upregulated in highly metastatic ACC cells and markedly enriched in their derived exosomes. Single-cell RNA sequencing was employed to comprehensively map the tumor microenvironment (TME), revealing robust intercellular communication between epithelial cells and cancer-associated fibroblasts (CAFs). Mechanistically, S100A9-enriched exosomes reprogrammed normal fibroblasts, resulting in the acquisition of an activated CAF phenotype characterized by the upregulation of FAP and α-SMA expression, and enrichment of IL-17, TNF-α, and NF-κB signaling pathways. Functionally, these exosome-educated CAFs promoted the epithelial-mesenchymal transition in ACC cells and facilitated lung metastasis in vivo via an IL-17-dependent signaling axis. Overall, these findings establish exosomal S100A9 as a crucial mediator of TME reprogramming, suggesting that targeting the S100A9-IL-17 axis may serve as a promising therapeutic strategy for disrupting ACC lung metastasis.