Intrinsic STING of CD8 + T cells regulates self-metabolic reprogramming and memory to exert anti-tumor effects.

Abstract

Background: Our team has previously found that the stimulator of interferon genes (STING) plays a more significant anti-tumor role in host immune cells than in tumor cells. Although STING is necessary for CD8 + T cells to exert immunological activity, its effect on CD8 + T cells remains debatable. In this study, we used both in vitro and in vivo models to explore the metabolic effects of STING on CD8 + T cells.

Methods: Peripheral blood lymphocytes were procured from non-small cell lung cancer (NSCLC) patients receiving anti-PD-1 therapy to investigate the correlation between STING expression levels, CD8 + T-cell subsets, and immunotherapy efficacy. STING knockout (STING-KO) mice were used for in vivo studies. RNA-seq, seahorse, flow cytometry, electron microscopy, qPCR, immunofluorescence, western blotting, and immunoprecipitation were performed to explore the underlying mechanisms of STING in regulating CD8 + T cell function.

Results: We discovered that the expression level of STING in immune cells exhibited a significant correlation with immunotherapy efficacy, as well as with the proportion of central memory CD8 + T cells. Moreover, we found that the loss of the STING gene results in a reduction in the number of mitochondria and a change in the metabolic pathway selection, thereby inducing excessive glycolysis in CD8 + T cells. This excessive glycolysis generates high levels of lactate, which further inhibits IFN-γ secretion and impacts memory T cell differentiation. Correcting the glycolysis disorder partially restored function and IFN-γ secretion, rescued the central memory CD8 + T subset, and improved immunotherapy in STING-KO mice. This provides a new treatment strategy for patients with low STING expression and a poor response to immunotherapy.

Conclusion: Intrinsic STING of CD8 + T cells affects their function through the HK2/Lactate/IFN-γ axis and affects memory differentiation by regulating glycolysis.