Blocking GPNMB may halt triple-negative breast cancer progression

Metastasis is the leading cause of cancer-related deaths and its progression is linked to changes within the tumour microenvironment (TME). In triple-negative breast cancer (TNBC) – an aggressive subtype lacking oestrogen receptor (ER), progesterone receptor (PR) and HER2 expression – these changes are particularly crucial.

Now, a new study by researchers at the University of Tsukuba have identified Glycoprotein non-metastatic melanoma protein B (GPNMB) as a driver of tumour progression in TNBC. This glycoprotein, found in high levels on TNBC cells, reshapes the TME by reprogramming macrophages into immunosuppressive tumour-associated macrophages (TAMs). These TAMs dampen the immune system’s response – enabling cancer growth and spread.

The role of sialic acid modifications

A distinctive feature of GPNMB in cancer cells is its cancer-specific sialic acid modification. This modification allows GPNMB to bind selectively to Siglec-9 – an immune receptor present on macrophages. Once connected, this interaction pushes macrophages toward an immunosuppressive phenotype – further fuelling tumour progression.  

Driving EMT and a self-amplifying loop

The GPNMB-Siglec-9 interaction not only suppresses immunity but also enhances epithelial-mesenchymal transition (EMT) – a process that makes cancer cells more mobile and invasive. GPNMB also creates a self-reinforcing feedback loop that promotes its own expression. This loop helps spread immunosuppressive TAMs throughout the TME – which improves cancer’s ability to metastasise.

In experimental mouse models, blocking GPNMB or Siglec-E (the murine equivalent of Siglec-9) significantly reducedIL-6-driven EMT and metastasis. These findings highlight the GPNMB-Siglec-9 pathway as a main driver of TNBC progression and resistance to current therapies.

Implications for future treatments

By discovering this mechanism, GPNMB-Siglec-9 axis becomes a promising target for next-generation immunotherapies. Interventions that disrupt this interaction could restore immune activity and reduce tumour invasiveness – which could improve outcomes for patients facing TNBC.