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Here, we identify lactate\u2010driven lactylation of STING at lysine 370 (K370), a primate\u2010conserved site, as a metabolic checkpoint restraining STING activation. Mechanistically, K370 lactylation directly weakens STING\u2010TBK1 interaction. In parallel, K370 lactylation rewires STING ubiquitin linkage preference by increasing K48\u2010 and decreasing K63\u2010linked ubiquitination, thereby limiting protein stability and oligomerization. Moreover, K370 lactylation weakens the interaction between STING and the COPII component SEC24A, impairing ER\u2010to\u2010Golgi trafficking\u2014a spatial step that normally amplifies STING\u2010TBK1 phosphorylation and downstream signaling cascades. Conversely, inhibition of lactate production diminishes K370 lactylation, restores STING\u2010TBK1 association, stabilizes STING, and permits efficient ER\u2010to\u2010Golgi 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\u20101 blockade in patient\u2010derived 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\u2010targeted metabolic intervention with STING\u2010based immunotherapy.<\/jats:p>","DOI":"10.1002\/advs.77209","type":"journal-article","created":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T17:52:27Z","timestamp":1786816347000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Lactate\u2010Induced K370 Lactylation of STING Inhibits STING\u2010TBK1 Signaling and Dampens Anti\u2010Tumor Immunity"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-6499-1201","authenticated-orcid":false,"given":"Yueyao","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Neurosurgery Shanghai East Hospital School of Medicine Tongji University  Shanghai 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