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

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.