Harnessing cGAS‐STING Pathway for Cancer Immunotherapy: From Bench to Clinic

Abstract

Recent advances in cancer immunotherapy have accomplished clinical successes in certain cancer models over the past decade. However, cancer treatments with adoptive cell transfer or immune checkpoint blockade (ICB) have shown critical limitations against solid tumors, which comprise the majority of human cancers. Thus, novel cancer immunotherapy which harnesses innate immunity process may be required in these tumor types. Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, one of the innate immune sensors, has gained interest in the field of immuno-oncology as activation of this pathway can drive both innate and adaptive immune responses among immunosuppressive tumor microenvironments. Recently, various cGAS-STING-activating strategies have been intensively investigated to achieve durable and widespread therapeutic responses in in vivo models. These meaningful preclinical outcomes have enabled several clinical trials. This review discusses agents targeting various aspects of the cGAS-STING pathway in cancer immunotherapy from benchtop to bedside. Moreover, various approaches to improve the clinical feasibility of cGAS-STING-activating strategies are delineated.

Cancer vaccines in the clinic

“…While TLR‐activating adjuvants are common in the clinical space, those that target other pathways, such as cyclic GMP‐AMP synthase stimulator of interferon genes (cGAS‐STING), Nod‐like receptor (NLR), and Rig‐I‐like receptor (RLR), are emerging as promising options for adjuvant combinations. The cGAS‐STING pathway is a cytosolic DNA sensing pathway of particular interest, since in recent years it has been shown to play a major role in tumor control 109–111 . Agents that act on this pathway stimulate type I interferon production in tumors, which drives downstream events including maturation of critical subsets of APCs (cDC1s), recruitment of T cells, and cross‐presentation to generate effective CD8+ T cells.…”

“…The cGAS‐STING pathway is a cytosolic DNA sensing pathway of particular interest, since in recent years it has been shown to play a major role in tumor control. 109 , 110 , 111 Agents that act on this pathway stimulate type I interferon production in tumors, which drives downstream events including maturation of critical subsets of APCs (cDC1s), recruitment of T cells, and cross‐presentation to generate effective CD8+ T cells. However, their instability, poor membrane permeability, and toxicity have precluded their effective use as systemic agents.…”

In situ administration of STING-activating hyaluronic acid conjugate primes anti-glioblastoma immune response

“…Recently, STimulator of INterferon Genes (STING) has been identified as a potential “druggable” immunotherapeutic target for cancer treatment [ [17] , [18] , [19] ]. STING is an endoplasmic reticulum-associated homodimer protein and the receptor for 2′,3′-cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) [ 20 ].…”

Encapsulation of Platinum Prodrugs into PC7A Polymeric Nanoparticles Combined with Immune Checkpoint Inhibitors for Therapeutically Enhanced Multimodal Chemotherapy and Immunotherapy by Activation of the STING Pathway

“…[ 3 ] As one of the most promising strategies to enhance the immunotherapeutic effect, recent studies have indicated the activation of the stimulator of interferon genes (STING) pathway. [ 4 ]…”