STING activation in cancer immunotherapy

Abstract

Cancer immunotherapy modulates and leverages the host immune system to treat cancer. The past decade has witnessed historical advancement of cancer immunotherapy. A myriad of approaches have been explored to elicit or augment anticancer innate immunity and/or adaptive immunity. Recently, activation of stimulator of interferon (IFN) genes (STING), an intracellular receptor residing in the endoplasmic reticulum, has shown great potential to enhance antitumor immunity through the induction of a variety of pro-inflammatory cytokines and chemokines, including type I IFNs. A number of natural and synthetic STING agonists have been discovered or developed, and tested in preclinical models and in the clinic for the immunotherapy of diseases such as cancer and infectious diseases. Cyclic dinucleotides (CDNs), such as cyclic dimeric guanosine monophosphate (c-di-GMP), cyclic dimeric adenosine monophosphate (c-di-AMP), and cyclic GMP-AMP (cGAMP), are a class of STING agonists that can elicit immune responses. However, natural CDNs are hydrophilic small molecules with negative charges and are susceptible to enzymatic degradation, leading to low bioavailability in target tissues yet unwanted toxicities and narrow therapeutic windows. Drug delivery systems, coupled with nucleic acid chemistry, have been exploited to address these challenges. Here, we will discuss the underlying immunological mechanisms and approaches to STING activation, with a focus on the delivery of STING agonists, for cancer immunotherapy.

Keywords: Stimulator of interferon genes (STING); cancer immunotherapy; cyclic GMP-AMP synthase (cGAS); cyclic dinucleotides; drug delivery; immunostimulatory adjuvants.

Figure 1

STING activation for cancer immunotherapy. (A) The cGAS-STING signaling pathway that mediate the cytosolic nucleic acid sensing and can be activated to elicit antitumor immune responses for cancer immunotherapy. Reprinted from , copyright (2017) Elsevier Ltd.. (B) Representative biomaterials that have been exploited to delivery STING agonists, including CDNs. (C) Schematic description of delivering STING agonists, via intratumoral vaccination or lymphoid vaccination, to elicit innate and adaptive antitumor immune responses. cGAS: cyclic GMP-AMP synthase; CDN: cyclic di-nucleotide; IFN: interferon; STING: stimulator of interferon genes; DC: dendritic cell; TCR: T cell receptor; MHC-I: major histocompatibility complex type I.

Figure 2

The chemical structures of representative STING agonists.

Figure 3

Polymersome-based CDN delivery for cancer immunotherapy. a) Schematic illustration of using pH-responsive diblock copolymers to formulate 2′3′-cGAMP-loaded endosomolytic polymersomes. b) Schematic description of intracellular uptake of the intracellular delivery of 2′3′-cGAMP via polymersomes (STING-NPs), the endosomal release of 2′3′-cGAMP from STING-NPs, and the endosomal escape of 2′3′-cGAMP to the cytosol for STING activation. Reprinted from , copyright (2019) Nature Publishing Group.

Figure 4

Schematic illustration of an implantable biomaterial scaffold that co-delivered CAR-T cells and CDNs for synergistic tumor immunotherapy. a) The scaffold that was loaded with CAR-T cells and microspheres of STING agonists interact with the tumor bed. b) The Macro- and microscope image of the porous alginate matrices that are functionalized with c-di-GMP-loading mesoporous silica microparticles. Reprinted from , copyright (2017) American Society for Clinical Investigation.

Figure 5

Intrinsically STING-activating nanoparticles for tumor immunotherapy. a) Schematic illustration of a series of polymer nanoparticles that were screened for immunostimulation and the generation of strong antigen specific CTL responses when loaded with a model antigen ovalbumin (OVA). b) Quantitative comparison of antigen specific CTL responses elicited by different polymer nanoparticles. Reprinted from copyright (2017) Nature Publishing Group.