In cancer cells, pyruvate generated through aerobic glycolysis is preferentially converted into lactate. Here, we examined the impact of aerobic glycolysis on innate immune regulation within the tumor microenvironment. We identified lactate as a potent suppressor of stimulator of interferon genes (STING)-mediated innate immune signaling. Lactate directly bound the cyclic GMP-AMP (cGAMP)-binding domain of STING, thereby inhibiting cGAMP binding, STING activation, and interferon regulatory factor 3 (IRF3)-dependent cytokine expression. Mechanistically, activation of epidermal growth factor receptor (EGFR) promoted phosphorylation of lactate dehydrogenase A (LDHA) by pyruvate kinase M2 (PKM2) at serine 161 (S161). This increased LDHA activity and lactate production, which suppressed immune cell infiltration and promoted tumor growth. Pharmacological PKM2 inhibition relieved lactate-mediated STING suppression, reduced tumor immune evasion, and synergized with anti-PD-1 therapy. In human glioblastoma, elevated LDHA S161 phosphorylation correlated with reduced STING activation, diminished cytotoxic immune cell infiltration, and poor survival. Thus, oncogenic signaling directs PKM2-generated pyruvate toward LDHA-mediated lactate production, which directly inhibits STING to silence innate immune activation.
