Trial watch: STING agonists in cancer therapy

Abstract

Stimulator of interferon response cGAMP interactor 1 (STING1, best known as STING) is an endoplasmic reticulum-sessile protein that serves as a signaling hub, receiving input from several pattern recognition receptors, most of which sense ectopic DNA species in the cytosol. In particular, STING ensures the production of type I interferon (IFN) in response to invading DNA viruses, bacterial pathogens, as well as DNA leaking from mitochondria or the nucleus (e.g., in cells exposed to chemotherapy or radiotherapy). As a type I IFN is critical for the initiation of anticancer immune responses, the pharmaceutical industry has generated molecules that directly activate STING for use in oncological indications. Such STING agonists are being tested in clinical trials with the rationale of activating STING in tumor cells or tumor-infiltrating immune cells (including dendritic cells) to elicit immunostimulatory effects, alone or in combination with a range of established chemotherapeutic and immunotherapeutic regimens. In this Trial Watch, we discuss preclinical evidence and accumulating clinical experience shaping the design of Phase I and Phase II trials that evaluate the safety and preliminary efficacy of STING agonists in cancer patients.

Keywords: CDK4/CDK6 inhibitors; CGAS; DNA damage response; PARP1; exosomes; immune checkpoint blockers; type I interferon.

Figure 1.

Overview of STING signaling in cancer cells. Accumulation of double-stranded DNA (dsDNA) in the cytosol of cancer cells responding to some chemotherapeutics or radiation therapy boosts the enzymatic functions of cyclic GMP-AMP synthase (CGAS), resulting in the cyclic GMP-AMP (cGAMP)-dependent oligomerization and activation of stimulator of interferon response cGAMP interactor 1 (STING1, best known as STING) at the endoplasmic reticulum (ER). Activated STING promotes a TANK binding kinase 1 (TAK1)-dependent signal transduction cascade that initiates interferon regulatory factor 3 (IRF3)- and NF-κB-dependent transcription, potentially culminating with the secretion of numerous cytokines including type I interferon (IFN), interleukin 6 (IL-6) and tumor necrosis factor (TNF). CDN, cyclic dinucleotide; IκBα (official name: NFKBIA), NFKB inhibitor alpha; IKKα (official name: CHUK), component of inhibitor of nuclear factor-kappa B kinase complex; IKKβ (official name: IKBKB), inhibitor of nuclear factor-kappa B kinase subunit beta; PARP, poly(ADP-ribose) polymerase.