Rao et al. found that lactylation stimulates the proteasomal degradation of cGAS independent of ubiquitin, which is compromised by phosphorylation of PSMA4 via disrupting its association with cGAS. Lactylation rewires PIK3CB activity and impairs ULK1-driven phosphorylation of PSMA4. Consequently, lactylation of cGAS sustains tumor growth and indicates the prognosis of LUAD.