Effect of intrinsic STING of CD8+T cells on self-metabolic reprogramming and anti-tumor effects.

e20062 Background: Many preclinical studies have demonstrated that STING agonists have effective anti-tumor effects, but their adverse effects prevent practical use. Previous research by our team has demonstrated that STING has a more significant anti-tumor role in host immune cells than tumor cells, and the level of STING mRNA is associated with the outcome of immunotherapy in non-small cell lung cancer. Although STING is necessary for CD8 + T cells to exert immunological activity, its effect on CD8 + T cells is debatable. Therefore, we will concentrate on the particular roles of STING in CD8 + T cells. Methods: We used in vitro and in vivo models to confirm the influence of STING on CD8 + T cell function. We examined the impact of STING on CD8 + T cell metabolic function using RNA-seq, Seahorse, flow, electron microscopy, and other techniques. STING knockout mice were used to study the effect of competitive inhibition of glycolytic products during immunotherapy. In addition, we collected peripheral blood immune cells from 30 immunotherapy patients to examine the correlation between immune cell glycolysis levels and immunotherapy efficacy. Results: RNA-seq showed significant changes in signaling pathways such as glycolysis/glycogen synthesis, oxidative phosphorylation, tricarboxylic acid cycle, and one carbon unit in STING-/- CD8 + T cells. In vitro experiments revealed that the inactivation of the STING gene reduced the number of mitochondria, altered the choice of metabolic pathways, and impaired the anti-tumor ability. Flow results showed that the mean fluorescence intensity of mitochondria in STING-/- CD8 + T decreased. Seahorse experiment showed that STING-/- CD8 + T glycolysis was enhanced, and oxidative phosphorylation was decreased. Meanwhile, the content of lactic acid in the culture supernatant of STING-/- CD8 + T increased dramatically, the high level of lactic acid further inhibited the proliferation of CD8 + T and the secretion of IFN-γ. Competitive inhibition of the glycolysis process or lactic acid formation can save the function of STING-/- CD8 + T cells and the secretion of IFN-γ, save the immunotherapy effect of STING-/- mice. This provides a new therapeutic idea for patients with low STING expression and poor immunotherapy response. In the peripheral blood immune cells of immunotherapy patients, we observed a negative correlation between the mRNA levels of glycolysis-associated molecules and STING. Additionally, we found a correlation between the levels of glycolysis-associated molecules in immune cells and immunotherapy efficacy outcomes. Conclusions: Our study is the first to explore the effect of STING on the metabolic process in CD8 + T cells. Intervening in the metabolic process of STING-deficient CD8 + T can save the efficacy of immunotherapy.