Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity

TLDR

Tumor‑initiated T cell priming relies on IFN‑β produced by tumor‑resident dendritic cells. The authors propose that intratumoral delivery of STING agonists will activate the STING pathway and provide effective anti‑tumor therapy. Building on DMXAA’s efficacy, they synthesized cyclic dinucleotide derivatives that activate all human and murine STING alleles. Intratumoral injection of these agonists caused dramatic regression of established tumors, elicited systemic immunity that eliminated distant metastases, and established durable memory, indicating strong translational potential.

Abstract

Spontaneous tumor-initiated T cell priming is dependent on IFN-β production by tumor-resident dendritic cells. On the basis of recent observations indicating that IFN-β expression was dependent upon activation of the host STING pathway, we hypothesized that direct engagement of STING through intratumoral (IT) administration of specific agonists would result in effective anti-tumor therapy. After proof-of-principle studies using the mouse STING agonist DMXAA showed a potent therapeutic effect, we generated synthetic cyclic dinucleotide (CDN) derivatives that activated all human STING alleles as well as murine STING. IT injection of STING agonists induced profound regression of established tumors in mice and generated substantial systemic immune responses capable of rejecting distant metastases and providing long-lived immunologic memory. Synthetic CDNs have high translational potential as a cancer therapeutic.