Old dogs, new trick: classic cancer therapies activate cGAS

Abstract

The discovery of cancer immune surveillance and immunotherapy has opened up a new era of cancer treatment. Immunotherapies modulate a patient's immune system to specifically eliminate cancer cells; thus, it is considered a very different approach from classic cancer therapies that usually induce DNA damage to cause cell death in a cell-intrinsic manner. However, recent studies have revealed that classic cancer therapies such as radiotherapy and chemotherapy also elicit antitumor immunity, which plays an essential role in their therapeutic efficacy. The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) and the downstream effector Stimulator of Interferon Genes (STING) have been determined to be critical for this interplay. Here, we review the antitumor roles of the cGAS-STING pathway during tumorigenesis, cancer immune surveillance, and cancer therapies. We also highlight classic cancer therapies that elicit antitumor immune responses through cGAS activation.

Fig. 1. The cGAS-STING pathway.

Abnormal localization of DNA in the cytosol elicits an immune response through the cGAS-STING pathway. Cytosolic DNA derives from exogenous (pathogens and dead cells) and endogenous (genome instability or mitochondrial damage) sources. cGAS binds to DNA in the cytosol and converts ATP and GTP into 2′3′-cGAMP. cGAMP then binds to STING on the ER to trigger STING trafficking to vesicles. cGAMP-bound STING activates the downstream kinases TBK1 and IKK to activate the transcription factors IRF3 and NF-κB, respectively. These transcription factors induce expression of type I IFNs and cytokines, which propagate the immune response in an autocrine and paracrine manner.

Fig. 2. Antitumor roles of cGAS.

a Premalignant cells acquire DNA damage during tumorigenesis, subsequently forming micronuclei. DNA in micronuclei are exposed to the cytosol and activate cGAS. cGAS induces cytokines and promotes SASP, which enhances senescence and promotes immune cell-mediated clearance of premalignant cells. b Tumor-derived DNA from dead cancer cells activate cGAS in dendritic cells. Stimulated dendritic cells prime spontaneous antitumor immunity by activating tumor-specific CD8⁺ T cells and NK cells to kill cancer cells. Similarly, tumor-derived cGAMP from cancer cells is transported to non-cancer cells and activates STING to induce antitumor immunity. c Classic cancer therapies (radiotherapy or chemotherapy) induce DNA damage and micronuclei formation. cGAS in cancer cells is activated by micronuclei to induce the production of type I IFNs and other cytokines; although these cytokines enhance antitumor immunity, they also up-regulate PD-L1 expression on cancer cells.

Fig. 3. cGAS-activating classic cancer therapies.

a Irradiation causes DNA breaks and damages. b Inhibiting key mediators of the DDR such as PARP1, ATM, and CHK1 leads to accumulation of DNA damage and generation of cytosolic DNA. c Interfering with replication halts replication forks, activating DDR and causing DNA breaks. Topoisomerase inhibitors, DNA crosslinkers, and antimetabolites stall replication forks. d Anti-microtubule drugs can induce chromosome mis-segregation, leaving a whole or a part of chromosome in the cytosol in the form of micronuclei or cytoplasmic chromatin fragments. All these different cellular perturbations can lead to cGAS activation.