From Bacteria to Cancer Therapy: New c-di-GMP Mechanism Offers Hope for Triple-Negative Breast Cancer

A groundbreaking study recently published in Signal Transduction and Targeted Therapy by the research team led by Hua Lu at the Tulane University School of Medicine has overturned the conventional understanding of the anticancer mechanism of c-di-GMP, a bacterial signaling molecule. The research reveals that c-di-GMP exerts potent anti-metastatic effects by directly targeting PSMD3 (26S proteasome non-ATPase regulatory subunit 3), independent of the STING pathway.

The study uncovers that PSMD3 is highly expressed in malignant tumors such as triple-negative breast cancer, acting as a novel activator of TBK1 kinase. It drives tumor metastasis by activating the NF-κB signaling pathway. c-di-GMP binds precisely to PSMD3 and blocks its interaction with TBK1, thereby inhibiting cancer cell migration. In mouse models, this molecule achieved near-complete suppression of lung metastasis with no observed significant toxicity.

This discovery not only establishes PSMD3 as a core novel prognostic biomarker for metastatic breast cancer but also points to a new avenue for the development of broad-spectrum anti-metastatic drugs. Given the favorable safety profile and specificity of c-di-GMP, this research provides a highly promising lead strategy for tackling triple-negative breast cancer—for which effective therapeutic targets are currently scarce—and multiple other highly metastatic cancers, with the potential to fill the gap in precision anti-metastatic therapy.

FOR DETAIL：https://www.nature.com/articles/s41392-025-02553-9

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