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.

Regulation of cGAS‐Mediated Immune Responses and Immunotherapy

“…STINGVAX coupled with ML‐RRS2‐CDA, an objectively structured phosphodiesterase‐resistant c‐di‐AMP (CDA) diastereomer with the phosphate joined linkage as cGAMP, has indicated improved antitumor adequacy contrasted with canonical c‐di‐AMP. Significantly, ML‐RR‐S2‐CDA comprehensively enacts distinctive human STING variations recognized by the 1000 Genomes Project 153. STINGVAX additionally upregulates PD‐L1 induction in tumors164; co‐treatment of STINGVAX with a PD‐1‐blocking immune response augments antitumor immunity and tumor regression 162.…”

“…The adaptive antitumor immunity is exceptionally reliant on innate immune responses to detect non‐self‐material by PRRs 152. Tumorigenesis generally relates to the development of cytosolic chromatin particles and micronuclei, expanding the likelihood of DNA release in an existing cell or cancerous cell‐inferred DNA uptake by DC 153. Instigation by the cGAS‐STING pathway invigorates IFN induction in diseased cells or DCs, initiating innate immune responses for anticancer immunity.…”

“…Currently, significant endeavors have been undertaken to locate a suitable cGAS‐STING agonist for anticancer drug advancement. The cGAS‐STING agonists incite diseased cell senescence and improve adaptive anti‐cancer resistance that might synergize with immunotherapies 153. Consequently, it is noteworthy to comprehend the advances of cGAS‐STING focusing on procedures with different immunotherapies, for example, RT, cancer vaccines, immune checkpoint inhibitors (ICI), therapeutic oncolytic virus (e.g., Talimogene laherparepvec (T‐VEC)) therapy in melanoma for enhanced expression of STING),155 chimeric antigen receptor T‐cell (CAR‐T) therapy employing single‐chain variable fragment (scFv), CAR‐modified T‐cell delivery through bioactive vehicles, and the use of combinatorial therapy by STING agonist cyclic di‐GMP (cdGMP) for tumor exclusion 156…”

“…[152] Tumorigenesis generally relates to the development of cytosolic chromatin particles and micronuclei, expanding the likelihood of DNA release in an existing cell or cancerous cell-inferred DNA uptake by DC. [153] Instigation by the cGAS-STING pathway invigorates IFN induction in diseased cells or DCs, initiating innate immune responses for anticancer immunity. IFN is an adaptable immune agent identified through cell senescence and inflammation immune response.…”

“…Significantly, ML-RR-S2-CDA comprehensively enacts distinctive human STING variations recognized by the 1000 Genomes Project. [153] STINGVAX additionally upregulates PD-L1 induction in tumors [164] ; co-treatment of STINGVAX with a PD-1-blocking immune response augments antitumor immunity and tumor regression. [162] Thus, cGAMP increases the antitumor impacts of the PD-L1 antibody.…”