What is it about?
Most cancer deaths are due to metastasis. We discovered that a protein called GPNMB, highly expressed in some triple-negative breast cancers, reprograms immune cells to support tumor growth. Tumor-derived GPNMB has a unique sugar pattern that binds Siglec-9, an immune “brake.” When GPNMB and Siglec-9 are both high, prognosis worsens. Blocking Siglec-9 and PD-1 together suppressed tumor spread in models, highlighting this pathway as a promising target for therapy.
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Why is it important?
Our work uncovers a previously unrecognized sugar-dependent pathway by which breast cancers control immune cells to promote metastasis. We show that tumor-derived GPNMB carries distinct sugar patterns that selectively engage the immune brake Siglec-9, creating a feed-forward loop of tumor-supporting macrophages. This is the first demonstration that glycosylation differences between tumor and immune cell proteins can dictate immune evasion. Because co-blocking Siglec-9 and PD-1 reduced tumor spread in models, our findings point to a new, timely therapeutic target for aggressive triple-negative breast cancer, with potential impact on improving survival.
Perspectives
Writing this article has been a deeply rewarding experience, as it grew out of years of collaboration between colleagues across cancer biology, immunology, and glycobiology. For me, the most exciting part was realizing how subtle sugar modifications on a single protein could fundamentally change the way immune cells behave in tumors. This project was not only scientifically challenging but also personally meaningful, because it connects basic molecular insights to potential new treatments for patients facing one of the most aggressive forms of breast cancer. I hope this work inspires others to look more closely at the “hidden language” of sugars in cancer and immunity, and I am grateful for the chance to contribute to this growing field.
Kunio Kawanishi
Showa Medical University School of Medicine
Read the Original
This page is a summary of: Tumor-expressed GPNMB orchestrates Siglec-9
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TAM polarization and EMT to promote metastasis in triple-negative breast cancer, Proceedings of the National Academy of Sciences, September 2025, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2503081122.
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