Why STING immunotherapy failed: Autophagy defects and neutrophils identified as causes

The reason therapies that activate the STING pathway, considered promising candidates for cancer immunotherapy, have not performed as well as expected in clinical trials has been identified. French researchers said defects in dendritic-cell autophagy and the influx of immunosuppressive neutrophils are key factors that hinder treatment efficacy.

According to BioOn on the 7th (local time), a research team from the French National Institute of Health and Medical Research (INSERM) published the findings in the journal Science Immunology.

The STING pathway is a key innate immune signaling system that, when abnormal DNA is detected in the cytoplasm, recruits immune cells by triggering the release of type I interferons and other molecules. Artificially activating it can prompt immune cells to attack tumors, making STING agonists a focus of interest as next-generation cancer drugs.

However, despite showing strong effects in animal studies, STING agonists have not achieved the expected results in clinical trials. The research team investigated the reasons for the failures using virus-like particles (VLPs) that precisely deliver cGAMP, a natural ligand of STING, to dendritic cells.

The findings showed that the anticancer effects of STING agonists do not depend on the type I interferon signaling pathway, which had previously been considered important. The team said that autophagy within dendritic cells determines whether treatment succeeds.

Autophagy is the process by which cells break down waste and maintain their internal environment. The researchers found that when dendritic cells have defective autophagy, they cannot properly present antigens and therefore fail to activate CD8-positive T cells that eliminate tumors.

In addition, when the STING pathway was activated in the presence of defective autophagy, it recruited large numbers of neutrophils to tumors and lymph nodes through the chemokine receptor CXCR2. Rather than attacking tumors, the recruited neutrophils secreted neutrophil elastase and highly expressed the immune checkpoint molecule PD-L1, suppressing the antitumor activity of T cells.

The research team said that removing neutrophils or inhibiting elastase activity substantially improved the tumor-suppressing effect of cGAMP-VLPs. This supports the role of neutrophils as a major factor limiting the efficacy of STING therapy.

The researchers concluded that strategies to improve the clinical efficacy of STING agonists should include assessing or restoring dendritic-cell autophagy before treatment and combining therapy with approaches to remove or reprogram neutrophils in the tumor microenvironment.