Role of the cGAS-STING pathway in cancer development and oncotherapeutic approaches

Abstract

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway mediates anti-microbial innate immunity by inducing the production of type I interferons (IFNs) and inflammatory cytokines upon recognition of microbial DNA. Recent studies reveal that self-DNA from tumors and by-products of genomic instability also activates the cGAS-STING pathway and either promotes or inhibits tumor development. This has led to the development of cancer therapeutics using STING agonists alone and in combination with conventional cancer treatment or immune checkpoint targeting. On the other hand, for cancers lacking the cGAS-STING pathway and thus a regular innate immunity response, oncolytic virus therapy has been shown to have therapeutic potential. We here review and discuss the dichotomous roles of the cGAS-STING pathway in cancer development and therapeutic approaches.

Keywords: STING; cGAS; cancer; immune therapy; oncolytic virus.

Figure 1. CDNs activate the cGAS‐STING pathway and induce production of cytokines

cGAS synthesizes 2′3′‐cGAMP (cyclic [G(2′,5′)pA(3′,5′)p]) upon engaging with cytosolic DNA from bacteria, viruses, tumor cells or chromatin fragments. 2′3′‐cGAMP and bacterial c‐di‐AMP (bis‐(3′–5′) cyclic diadenylic acid), c‐di‐GMP (bis‐(3′‐5′) cyclic diguanylic acid), and 3′3′‐cGAMP (cyclic [G(3′,5′)pA(3′,5′)p]) activate STING and stimulate its translocation from endoplasmic reticulum (ER) via Golgi apparatus to perinuclear microsomes. Active STING coordinates multiple phosphorylation events involving TBK1 kinase to induce nuclear translocation of IRF3 and TBK1, leading to transcriptional induction of cytokines, including IFNs. ML‐RR‐S2‐CDA (Rp, Rp dithio diastereomer cyclic [A(2′,5′)pA(3′,5′)p), is a synthetic CDN that triggers STING activation for cancer therapy.

Figure 2. Model of the tumor suppressive roles of the cGAS‐STING pathway and possibilities of utilizing CDNs for tumor treatment

Cytoplasmic chromatin DNA activates the cGAS‐STING pathway and induces type I IFN and senescence‐associated secretory phenotype (SASP) production, which promote cellular senescence. Uptake of tumor‐derived DNA may lead to activation of the cGAS‐STING pathway in DCs and production of type I IFN, which regulates cross‐priming of CD8+ T cells for anti‐tumor immunity. Immune checkpoint pathways of PD‐L1/PD‐1 and B7/CTLA‐4 negatively regulate CD8+ T cell activity killing cancer cells. Combinatory treatments with CDNs augment the anti‐tumor efficacy of immune checkpoint inhibitors (anti‐PD‐1, ‐PD‐L1, ‐CTLA4 antibodies), radiation therapy, and chemotherapy.

Figure 3. Targeting cancer cells lacking the cGAS–STING pathway

Viral infection is suppressed by the innate immune response following cGAS–STING pathway activation. Cancer cells with a defective cGAS–STING pathway are susceptible to oncolytic virus infection. Virus replication and cell lysis result in tumor regression.