ACE2 acts as a tumor suppressor in breast cancer by inhibiting progression via the TGF-β1/Smad pathway and potentiating immune checkpoint blockade.

Angiotensin-converting enzyme 2 (ACE2) is acknowledged for its crucial function as a receptor in pneumonia. However, emerging evidence suggests that ACE2 also plays a significant role in tumor progression, but its regulatory mechanisms in breast cancer remain unclear. This study aims to elucidate the clinical significance and underlying mechanism of ACE2 in breast cancer. Our findings demonstrate that ACE2 expression is significantly downregulated in breast cancer tissues compared to adjacent normal tissues, exhibiting subtype-specific patterns: most pronounced in Luminal A and Luminal B, modest in Basal-like, and unchanged in Her2-positive tumors. ACE2 downregulation in these subtype-specific breast cancers may indicate a poor prognosis. Furthermore, this study identified that ACE2 is positively correlated with infiltration of various immune cells, especially CD4 T cells and CD8 T cells, shaping an immune-active microenvironment. In vitro and in vivo, ACE2 overexpression can suppress proliferation, migration, and invasion of breast cancer cells. Mechanistically, ACE2 inhibits TGF-β1/Smad2 signaling, epithelial-mesenchymal transition (EMT), and other pro-oncogenic pathways. Moreover, ACE2 high expression in breast cancer could enhance anti-tumor immunity and improve response to anti-PD-L1 therapy, exhibiting an increased tumor infiltration of cytotoxic CD8 T cells. Collectively, ACE2 acts as a tumor suppressor and immune modulator in breast cancer, inhibiting progression via TGF-β1/Smad2 and potentiating immune checkpoint blockade, representing a potential therapeutic target.