Crosstalk between cGAS-STING pathway and autophagy in cancer immunity

Abstract

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is critical in cancer immunity. Autophagy is a highly conserved process that is responsible for the degradation of cytoplasmic material and is involved in both innate and adaptive immunity. Recently, cGAS-STING and autophagy have been shown to be interconnected, which may influence the progression of cancer. Although cGAS-STING and autophagy have been shown to be interrelated in innate immunity, little has been reported about cancer immunity. As cancer immunity is key to treating tumors, it is essential to summarize the relationship and interactions between the two. Based on this, we systematically sorted out the recent findings of cGAS-STING and autophagy in cancer immunity and explored the interactions between cGAS-STING and autophagy, although these interactions have not been extensively studied. Lastly, we provide an outlook on how cGAS-STING and autophagy can be combined, with the hope that our research can help people better understand their potential roles in cancer immunity and bring light to the treatment of cancer.

Keywords: antitumor; autophagy; cGAS-STING; cancer; immunity.

Figure 1

Schematic illustration of the crosstalk between the cGAS-STING pathway and autophagy in cancer immunity. The figure was created with BioRender (https://biorender.com/).

Figure 2

In this model, the cGAS interacts with the dsDNA via liquid-liquid phase separation, which activates the cGAS. STING is activated in the ER when cGAMP is generated in response to the concentration of the reactants. As STING is transferred to the Golgi apparatus, TBK1 is recruited to activate IRF3. When IRF3 is activated, it enters the nucleus and functions with NF-κB to produce type I IFN. The figure was created with BioRender (https://biorender.com/).

Figure 3

Several steps are involved in canonical autophagy: (1) initiation; (2) nucleation or phagosome extension; (3) maturation; (4) autophagosome formation; (5) autophagosome and lysosome formation; (6) degradation. The figure was created with BioRender (https://biorender.com/).

Figure 4

The upstream and downstream of the cGAS-STING pathway, including STING proteins, trigger autophagy by the following roughly divided mechanisms: cGAS binds to dsDNA to form liquid-phase condensates. (1) cGAS interacts with Beclin1 and triggers canonical autophagy; (2) cGAS binds to LC3 to induce non-canonical autophagy; (3) cGAS binds to dsDNA and recruits ATG, LC3, and P62 to participate in canonical autophagy; (4) STING leads to ER stress, mTOR inactivation, and coordinates autophagy; (5) STING stimulates RAB22A-mediated non-canonical autophagy derived from the ER; (6) STING recruits ATG16L1 to lipidated LC3, induces non-canonical autophagy. The figure was created with BioRender (https://biorender.com/).