Lactate‐Induced K370 Lactylation of STING Inhibits STING‐TBK1 Signaling and Dampens Anti‐Tumor Immunity
- 1Department of Neurosurgery Shanghai East Hospital School of Medicine Tongji University Shanghai China
- 2State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center Shanghai East Hospital School of Medicine Tongji University Shanghai China
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.
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BibTeX
@article{wu2026lactateinduced,
title = {{Lactate‐Induced K370 Lactylation of STING Inhibits STING‐TBK1 Signaling and Dampens Anti‐Tumor Immunity}},
author = {Yueyao Wu and Jingzhe Wang and Xu Chen and Yuntong Yang and Ping Wei and Han Xie and Honghao Wang and Chunyu Zhang and Siyi Xu and Qi Wang and Chunlong Zhong and Jing Zhang},
journal = {Advanced Science},
year = {2026},
month = aug,
doi = {10.1002/advs.77209},
url = {https://doi.org/10.1002/advs.77209},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Lactate‐Induced K370 Lactylation of STING Inhibits STING‐TBK1 Signaling and Dampens Anti‐Tumor Immunity
AU - Yueyao Wu
AU - Jingzhe Wang
AU - Xu Chen
AU - Yuntong Yang
AU - Ping Wei
AU - Han Xie
AU - Honghao Wang
AU - Chunyu Zhang
AU - Siyi Xu
AU - Qi Wang
AU - Chunlong Zhong
AU - Jing Zhang
PY - 2026
DA - 2026/08/15
JO - Advanced Science
DO - 10.1002/advs.77209
UR - https://doi.org/10.1002/advs.77209
AB - 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.
SN - 2198-3844
ER -