Lactate-Induced K370 Lactylation of STING Inhibits STING-TBK1 Signaling and Dampens Anti-Tumor Immunity.

Authors

Yueyao Wu, Jingzhe Wang, Xu Chen, Yuntong Yang, Ping Wei, Han Xie, Honghao Wang, Chunyu Zhang, Siyi Xu, Qi Wang, Chunlong Zhong, Jing Zhang

Published in

Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e77209. Aug 15, 2026. Epub Aug 15, 2026.

Abstract

The stimulator of interferon genes (STING) pathway represents a central component of innate anti-tumor immunity; however, the efficacy of STING-targeted therapies is frequently limited by tumor-intrinsic resistance mechanisms. Here, we identify lactate-driven lactylation of STING at lysine 370 (K370), a primate-conserved site, as a metabolic checkpoint restraining STING activation. Mechanistically, K370 lactylation directly weakens STING-TBK1 interaction. In parallel, K370 lactylation rewires STING ubiquitin linkage preference by increasing K48- and decreasing K63-linked ubiquitination, thereby limiting protein stability and oligomerization. Moreover, K370 lactylation weakens the interaction between STING and the COPII component SEC24A, impairing ER-to-Golgi trafficking-a spatial step that normally amplifies STING-TBK1 phosphorylation and downstream signaling cascades. Conversely, inhibition of lactate production diminishes K370 lactylation, restores STING-TBK1 association, stabilizes STING, and permits efficient ER-to-Golgi translocation, thereby enabling robust type I interferon signaling upon pathway stimulation. Pharmacological LDHA inhibition potentiates STING signaling and enhances the therapeutic efficacy of STING agonism alone or in combination with PD-1 blockade in patient-derived tumor models and orthotopic glioblastoma mouse models. In conclusion, our findings identify STING K370 lactylation as a metabolic regulatory node restraining STING signaling and provide a rationale for combining lactate-targeted metabolic intervention with STING-based immunotherapy.

PMID:
42603295
Bibliographic data and abstract were imported from PubMed on 16 Aug 2026.

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