STING: a master regulator in the cancer-immunity cycle

Abstract

The aberrant appearance of DNA in the cytoplasm triggers the activation of cGAS-cGAMP-STING signaling and induces the production of type I interferons, which play critical roles in activating both innate and adaptive immune responses. Recently, numerous studies have shown that the activation of STING and the stimulation of type I IFN production are critical for the anticancer immune response. However, emerging evidence suggests that STING also regulates anticancer immunity in a type I IFN-independent manner. For instance, STING has been shown to induce cell death and facilitate the release of cancer cell antigens. Moreover, STING activation has been demonstrated to enhance cancer antigen presentation, contribute to the priming and activation of T cells, facilitate the trafficking and infiltration of T cells into tumors and promote the recognition and killing of cancer cells by T cells. In this review, we focus on STING and the cancer immune response, with particular attention to the roles of STING activation in the cancer-immunity cycle. Additionally, the negative effects of STING activation on the cancer immune response and non-immune roles of STING in cancer have also been discussed.

Fig. 1

DNA-driven cGAS-cGAMP-STING signaling mediates innate immune response. The left cell exhibits the main components of cGAS-cGAMP-STING signaling pathway and IFN signaling pathway, and the right cell shows that IFN could activate neighbor cells in a paracrine manner and cGAMP could be transferred to neighbor cells through GAP junction

Fig. 2

Activation of STING positively regulates each step of cancer-immunity cycle

Fig. 3

The positive and negative roles of STING activation in antitumor immune response. On the one hand, STING facilitates antitumor immune response through promoting the infiltration of effector cells and eradication of tumor cells. On the other hand, constant STING activation may hamper immune response by inducing the infiltration of immune suppressive cells, such as Treg and MDSC, and upregulating the expression of PD-L1 on tumor cells and PD-1 on T cells. Moreover, STING activation is associated with the enhanced activity of IDO, an enzyme catalyzing the transformation of tryptophan into kynurenine. Diminished tryptophan restricts the proliferation of T cells whereas elevated kynurenine promotes differentiation of Tregs but hampers antigen presenting ability of DCs. Additionally, aberrant STING activation also directly inhibits T cell proliferation and even promotes apoptosis of lymphocytes