Combined inhibition of S100A4 and TIGIT suppresses late-stage breast cancer metastasis.

It is estimated that ∼170,000 women in the US live with metastatic breast cancer in 2025. While multiple treatment options exist for metastatic breast tumor, none of them are curative. Here, we investigate the mechanism through which S100A4 promotes breast cancer metastases and report that S100A4 is a critical regulator of neutrophil infiltration into the lung to establish a premetastatic niche (PMN). We show that a novel S100A4 blocking antibody (S100A4-11) suppresses neutrophil infiltration and relieves TIGIT-mediated NK cell inhibition in the lung, leading to significantly reduced lung metastases in two different mouse models. When the treatment is initiated after the PMN formation, simulating most clinical situations, S100A4-11 treatment as a monotherapy is not sufficient to block lung metastases. However, a novel combination of anti-S100A4 and anti-TIGIT treatment significantly suppresses late-stage lung metastases by increasing CD8+ T and NK cell infiltration and activation in the lung. In summary, this study provides compelling evidence that S100A4 functions systemically and locally to promote breast cancer metastases and supports developing S100A4-11 as a novel immunotherapy to suppress breast cancer metastases.