Unveiling the crossroads of STING signaling pathway and metabolic reprogramming: the multifaceted role of the STING in the TME and new prospects in cancer therapies

Abstract

The cGAS-STING signaling pathway serves as a critical link between DNA sensing and innate immunity, and has tremendous potential to improve anti-tumor immunity by generating type I interferons. However, STING agonists have shown decreasing biotherapeutic efficacy in clinical trials. Tumor metabolism, characterized by aberrant nutrient utilization and energy production, is a fundamental hallmark of tumorigenesis. And modulating metabolic pathways in tumor cells has been discovered as a therapeutic strategy for tumors. As research concerning STING progressed, emerging evidence highlights its role in metabolic reprogramming, independent its immune function, indicating metabolic targets as a strategy for STING activation in cancers. In this review, we delve into the interplay between STING and multiple metabolic pathways. We also synthesize current knowledge on the antitumor functions of STING, and the metabolic targets within the tumor microenvironment (TME) that could be exploited for STING activation. This review highlights the necessity for future research to dissect the complex metabolic interactions with STING in various cancer types, emphasizing the potential for personalized therapeutic strategies based on metabolic profiling.

Fig. 1

Signaling mechanism of the canonical cGAS-STING pathway and its downstream effects in diseases. Exogenous DNA from virus, bacteria, dying cell and tumor cell, and endogenous mtDNA induced by radiation bind to cGAS, catalyzing the production of cGAMP. cGAMP activates STING, leading to its conformational change and trafficking from ER to Golgi. In the process, STING undergoes oligomerization and palmitoylation, which is essential for the recruitment of TBK1. TBK1 then phosphorylates STING for IRF3 activation. IRF3 then transfer to the nucleus and triggers type I IFN expression. STING activation also induces NF-κB signaling, leading to the production of pro-inflammatory cytokins such as TNF-α and IL- 6

Fig. 2

Mechanisms by which lipid metabolism regulates the STING signalling pathway. (1) LXR activation induced by cholesterol promote SMPDL3 A-catalyzed degradation of cGAMP, therefore inhibiting STING activation. (2) Lipotoxic molecules such as PUFAs and 7-HOCA induce mtDNA release, activating cGAS-STING signaling pathway. (3) SCFA engages GPR43, causing a rise in intracellular calcium and mtDNA release, inducing cGAS-STING signaling pathway. (4) cGAMP reduces ER cholesterol level, unlocking the retention of STING on ER, thus promoting its translocation. (5) SCAP and SREBP facilitate STING transport through physical connections. (6) Some lipid molecules disrupt the palmitoylation of STING through modification, inhibiting its activation. (7) PI4P promotes the post-Golgi transport of STING, enhancing its activity. (8) PI4P drives the formation of non-canonical autophagosomes that package and transport activated STING to immune cells

Fig. 3

The interplay between STING and glucose metabolism. NSUN2 functions as a glucose sensor in tumor cells, maintaining intracellular silence of STING. Itaconate inhibits STING activation through targeting its negative regulator Nrf2 or mtDNA release induced by mitochondrial dysfunction. AMPK senses decreased glucose level, facilitating STING activation. In dendritic cells, ATP produced in glycolysis activates STING signaling, which also enhances glycolysis, establishing a positive feedback loop. Some transcription regulators of glycolysis-related genes are induced by STING activation, leading to glycolic reprogramming, further influencing the progress of multiple diseases

Fig. 4

Mechanism through which STING activation leads to insulin resistance. STING promotes Pax6, inhibiting to the glucose stimulated secretion of insulin. The activation of STING-IRF3 pathway induces the expression of AIG1, which promotes insulin secretion through activating GPR40 receptor. TBK1 can directly phosphorylate Irβ, blocking the activity of the insulin receptor tyrosine kinase and the subsequent downstream signaling pathways. On the one hand, IRF3 phosphorylates IRs1 through interacting with JMJD8, on the other hand, IRF3 blocks PI3 K-AKT pathway, which is considered essential in insulin signaling. The activation of STING-NF-κB drives the production of pro-inflammatory cytokines, such as TNF-α and IL- 6, promoting insulin resistance