Study Identifies ENPP1 Protein as Key to Improving Breast Cancer Immunotherapy

Researchers from Stanford University and the Arc Institute have identified a protein called ENPP1 that they say can be used as a biomarker for breast cancer stratification as well as a target for immunotherapy.

ENPP1, produced by both cancer and healthy cells around the tumor, acts as an on/off switch controlling immunotherapy resistance and subsequent metastases. High levels of ENPP1 correlated with poor responses to immunotherapy and increased chances of metastases. The research suggests that ENPP1 could be a valuable predictive marker for patient responses, leading to more effective immunotherapies.

To convert "cold" tumors into "hot" ones, the team explored cGAMP, a molecule produced when DNA is damaged in cancerous cells. However, ENPP1 was found to inhibit the immune response triggered by cGAMP, keeping tumors resistant to treatment. Mouse studies confirmed that removing ENPP1 or inhibiting its cGAMP-chewing ability resulted in decreased tumor growth and metastases by suppressing the STING pathway—an on/off switch for the immune response.

The findings, published in PNAS, provide insights into the clinical significance of ENPP1, suggesting its critical role in metastases and its impact on treatment outcomes. Clinicians may use ENPP1 levels to tailor breast cancer treatment, and drugs inhibiting ENPP1 are in clinical development, potentially enhancing the effectiveness of existing therapies.