The cGAS‒STING pathway in cancer immunity: mechanisms, challenges, and therapeutic implications

Abstract

Innate immunity represents the body's first line of defense, effectively countering the invasion of external pathogens. Recent studies have highlighted the crucial role of innate immunity in antitumor defense, beyond its established function in protecting against external pathogen invasion. Enhancing innate immune signaling has emerged as a pivotal strategy in cancer therapy. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is a key innate immune signal that activates the immune response and exerts antitumor effects; this is primarily attributed to the DNA receptor function of cGAS, which recognizes exogenous DNA to activate downstream STING signaling. This, in turn, promotes the activation of downstream targets such as IRF-3(Interferon Regulatory Factor 3) and NF-κB, leading to the secretion of type I interferons and proinflammatory cytokines, thereby increasing cellular immune activity. The activation of the cGAS-STING pathway may thus play a crucial role in enhancing anticancer immunity. In this paper, we reviewed the role of cGAS-STING signaling in anticancer immunity and its molecular mechanisms. Additionally, we briefly discuss the current applications of the cGAS-STING pathway in cancer immunity, summarize recent developments in STING agonists, and address the challenges facing the use of the cGAS-STING pathway in cancer therapy. Finally, we provide insights into the role of the cGAS‒STING pathway in cancer and propose new directions for cancer immunotherapy.

Keywords: Cancer immunity; Innate immunity; STING; cGAS.

Fig. 1

Schematic of the cGAS‒STING pathway. Canonical cGAS-STING Pathway. Cytosolic double-stranded DNA (dsDNA), originating from viruses, bacteria, necrotic cells, or other sources, activates cGAS, which catalyzes the synthesis of cGAMP from ATP and GTP. cGAMP subsequently binds to and activates STING, which, upon activation, recruits TBK1 and IKK. This recruitment leads to the phosphorylation of IRF3 and NF-κB, ultimately driving the expression of downstream inflammatory cytokines. Non-canonical STING Signaling. Upon DNA damage, ATM and PARP-1 are recruited and promote the assembly of an alternative STING signaling complex comprising IFI16, p53, and the E3 ubiquitin ligase TRAF6. Within this complex, TRAF6 mediates STING ubiquitination, leading to NF-κB activation

Fig. 2

Regulation of the cGAS-STING pathway in immune cells within the tumor microenvironment. (a) STING promotes the differentiation of CD4⁺ T cells into Th9 cells via GAMP/p70S6K signaling, leading to the secretion of IL-9 and subsequent tumor cell killing; (b) STING signaling drives the differentiation of CD4⁺ T cells into Th1 cells through IRF-3, resulting in the secretion of interferon-γ, which kills tumor cells; (c) STING signaling activates dendritic cells (DCs) by inducing the production of type I interferons, further activating CD8⁺ T cells; (d) STING signaling activates natural killer (NK) cells by promoting NLRP3, thereby enhancing tumor cell killing

Fig. 3

Role of the cGAS-STING pathway in cancer immunity. The cGAS-STING pathway plays a crucial role in tumor immunity. The key elements are as follows: (1) Enhanced antigen processing and presentation; (2) Promotion of T cell activation and infiltration; (3) Amplification of T cell- and NK cell-mediated tumor eradication; (4) Reprogramming of the immunosuppressive tumor microenvironment

Fig. 4

The application of the cGAS‒STING pathway in cancer therapy (1). STING agonists activate STING, leading to the recruitment and activation of immune-related cells, such as dendritic cells (DCs) and natural killer (NK) cells. In turn, these immune cells shape a tumor microenvironment that enhances the efficacy of CAR-T cell therapy; (2) Injection of a STING-based tumor vaccine into tumor tissues increases the infiltration of DCs, CD8 + T cells, and NK cells, as well as stimulates the secretion of IFN, thereby inducing a robust immune response; (3) A nanosatellite delivery system carrying the STING agonist cGAMP activates STING, leading to the recruitment of immune-related cells and the promotion of T cell activation. This enhances the efficacy of anti-PD-1 and anti-CTLA-4 antibodies in tumor elimination.; (4) The cGAS-STING pathway is closely linked to viral infections. Herpes simplex virus type 1 (HSV-1) activates the cGAS-STING pathway, whereas other viruses, including human papillomavirus type 18 (HPV18) and Kaposi’s sarcoma-associated herpesvirus (KSHV), suppress its activation