# Cyclic di-GMP suppresses cancer metastasis by targeting proteasome 26S subunit non-ATPase 3 independently of STING

## TL;DR

This study shows that the molecule c-di-GMP can stop cancer from spreading by targeting a protein called PSMD3, offering a new treatment approach for metastatic breast cancer.

## Contribution

The paper identifies PSMD3 as a novel target of c-di-GMP and reveals a new mechanism of action independent of STING.

## Key findings

- Cyclic di-GMP inhibits cancer metastasis, especially in breast cancer, with minimal toxicity.
- Cyclic di-GMP suppresses NF-κB signaling by binding to PSMD3 and disrupting its interaction with TBK1.
- PSMD3 is highly expressed in metastatic breast cancers, making it a promising therapeutic target.

## Abstract

Cancer metastasis is the primary cause of cancer-related mortality, yet effective treatments remain limited. There is an urgent need to develop novel therapeutic strategies to combat metastasis. In this study, we demonstrate that the bacterial intracellular signaling molecule cyclic di-GMP (c-di-GMP, or cdG) exerts a potent inhibitory effect on cancer metastasis, particularly in metastatic breast cancer, via both in vitro and in vivo models, with little toxicity to mice. Interestingly, this antimetastatic function is achieved by suppressing the NF-κB signaling pathway, which is important for cancer progression and metastasis, but independent of STING, a previously identified c-di-GMP sensor and NF-κB regulator in mammalian cells. Surprisingly, c-di-GMP inhibits NF-κB activity (p-p65) by directly binding to the proteasome 26S subunit non-ATPase 3 (PSMD3) that we identified as a new TBK1-binding activator, and disrupting the interaction between PSMD3 and TBK1. This PSMD3-TBK1 interaction boosts the phosphorylation and activation of TBK1, representing a noncanonical function of PSMD3 distinct from its established role in proteasomal degradation. Significantly, PSMD3 is highly expressed in malignant and metastatic breast cancers, particularly triple-negative breast cancer. The compelling evidence strongly suggests PSMD3 as a promising target for developing a therapy against metastatic breast cancer. These findings underscore the high potential of c-di-GMP as a safe and effective therapeutic agent for metastatic cancers by targeting the PSMD3-TBK1-NF-κB pathway.