Lactate Silences STING in Cancer Cells

STING is a protein that acts as a danger sensor inside cells. When it detects abnormal signals, it triggers a chain of events that lead to the production of interferons. These interferons then call immune cells to the site of a tumor. In many cancers, this alarm system is turned off, which lets the tumor grow without being attacked.

Scientists have found that a small molecule called lactate, which is made by rapidly dividing cancer cells, can attach to STING at a particular spot known as lysine 370. This attachment is a form of lactylation. The lactylation prevents STING from linking to its partner protein TBK1, a step needed to start the signaling process.

The modification also changes the way STING is tagged with ubiquitin chains. It increases the number of K48 chains, which mark the protein for breakdown, and reduces the number of K63 chains, which help keep the protein stable. Moreover, the lactylation blocks STING from moving from the endoplasmic reticulum to the Golgi apparatus, a journey that normally amplifies the signal.

As a result, the STING pathway stays silent even when it is stimulated by drugs. When researchers block the enzyme that produces lactate, STING can once again interact with TBK1 and travel to the Golgi. In mouse models of glioblastoma and in patient‑derived tumor samples, this restoration makes STING‑activating therapies more effective, especially when combined with PD‑1 blockade.