Abstract B005: STING is a cell-intrinsic metabolic checkpoint restricting aerobic glycolysis and OXPHOS by targeting HK2 and ATP5a

Abstract The evasion of antitumor immunity is a defining characteristic of cancer. STING, a proposed innate immune signaling adapter, plays a crucial role in eliciting antitumor immunity by integrating innate detection and adaptive immune surveillance. STING functions as an intrinsic tumor suppressor but is often downregulated in many human cancer types, and the mechanism by which STING exhibits intrinsic antitumor functions remains unclear. Here, we find that high STING impairs tumor cells growth by inhibiting both aerobic glycolysis and oxidative phosphorylation (OXPHOS) independently of its innate immune action. Knockout of STING in DLBCL cell lines leads to increased mitochondria membrane potential (MMP) and ATP generation, and decreased apoptosis. Mechanistically, STING inhibits hexokinase II (HK2) to obstruct its hexokinase function, and inhibits ATP5a which is a catalytic subunit of the mitochondrial ATP synthase complex responsible for the synthesis of ATP.Consequently, STING inhibits HK2 and ATP5a to limit both tumor aerobic glycolysis and OXPHOS, and enhance antitumor immunity in vivo. This work demonstrates that STING acts as a cell-intrinsic metabolic checkpoint that limits aerobic glycolysis and OXPHOS to exert antitumor functions. These findings hold significant implications for the advancement of STING-based treatment strategies to enhance antitumor immunotherapy. Citation Format: Rui Wang. STING is a cell-intrinsic metabolic checkpoint restricting aerobic glycolysis and OXPHOS by targeting HK2 and ATP5a [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B005.