Fueling the fire: aspartate deficiency primes and fuels STING activation
Haitao Jiang, Wenyan Wang, Yang-Xin Fu
Haitao Jiang, Wenyan Wang, Yang-Xin Fu
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Commentary

Fueling the fire: aspartate deficiency primes and fuels STING activation

Abstract

Cytosolic DNA sensing through the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway has emerged as a promising strategy to elicit antitumor immunity. However, clinical translation of STING agonists has been hindered by limited efficacy and dose-limiting inflammatory toxicity, highlighting that simply providing activating ligands is insufficient to achieve durable immune responses. In this issue of the Journal of Clinical Investigation, Liao et al. showed that intracellular aspartate availability critically shapes STING signaling responsiveness. Aspartate deficiency disrupted pyrimidine synthesis, induced mtDNA stress, and engaged a feed-forward Z-DNA binding protein 1 and receptor interacting serine/threonine kinase 1/3 axis. Rather than directly triggering immunity, this metabolic state primed DNA sensing and fueled downstream signaling, thereby enabling robust and sustained antitumor immune responses. Together, these findings position nucleotide metabolism as a key determinant of innate immune responsiveness and suggest that metabolic conditioning may enhance the efficacy of STING-targeted therapies.

Authors

Haitao Jiang, Wenyan Wang, Yang-Xin Fu

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Figure 1

Aspartate metabolism primes and fuels STING-mediated antitumor immunity.

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Aspartate metabolism primes and fuels STING-mediated antitumor immunity....
(Left) In an aspartate-sufficient state, de novo pyrimidine synthesis is efficient, preserving mitochondrial DNA (mtDNA) integrity within mitochondria. Minimal mtDNA is released into the cytosol, resulting in weak cGAS/STING pathway activation, limited type I interferon (IFN-I) production, and insufficient CD8+ T cell activation, ultimately leading to ineffective antitumor immunity. (Right) Aspartate deficiency impairs pyrimidine synthesis, causing nucleotide scarcity that destabilizes mtDNA and promotes its cytosolic release. Cytosolic mtDNA potentiates STING signaling and enables a feed-forward amplification circuit through the ZBP1–RIPK1/3 axis. This sustained signaling intensifies IFN-I production and CD8+ T cell–mediated antitumor immunity, thereby converting otherwise weak stimuli (low-dose STING agonists) or transient stimuli (radiotherapy and chemotherapy) into robust and sustained antitumor immune responses.