From energy metabolic homeostasis to immune remodeling: the role and therapeutic potential of STING signaling in the tumor microenvironment

Abstract The stimulator of interferon genes (STING) pathway is a core regulatory axis of innate immunity. By sensing cytoplasmic DNA, it activates the transcription of type I interferons and pro-inflammatory cytokines, playing a pivotal role in mediating anti-tumor immune responses. Accumulating evidence indicates that the biological functions of STING signaling extend well beyond immune regulation, engaging in extensive and dynamic crosstalk with energy metabolic homeostasis within the tumor microenvironment (TME). The bidirectional interplay forms a central mechanism that shapes the overall immune landscape of the TME. Here, we systematically review the mechanisms by which STING signaling interacts with four core energy metabolic pathways—glycolysis, oxidative phosphorylation, lipid metabolism, and glutamine metabolism—as well as key metabolic regulators. We clarify the critical role of STING as a hub that integrates cellular metabolic stress, energy status, and innate immune responses. Building on these findings, we further elaborate on the pathological significance of crosstalk between STING signaling and the energy metabolic network in TME remodeling. Finally, we highlight combinatorial anti-tumor therapeutic strategies that target key metabolic-immune intersections within this regulatory network, offering a theoretical framework and practical insights for developing novel therapies. In conclusion, the intricate and dynamic crosstalk between STING signaling and the core energy metabolic network establishes it as a critical node linking innate immunity with metabolic homeostasis, and strategically targeting these metabolic-immune intersections represents a promising avenue for developing more effective, combination-based anti-tumor therapies.