AARS1-mediated lactylation of STAT1 drives immune evasion.

Lactate accumulates in large amounts in tumor cells due to the Warburg effect. However, the role of lactate-mediated lactylation, a post-translational modification, in regulating tumor immunity remains unclear. Here, we report that lactate-driven lactylation of STAT1 K193 inhibits interferon (IFN)-γ signaling pathway-mediated tumor immunity. Mechanistically, AARS1 lactylates STAT1 K193 and inhibits its binding to JAK2 and phosphorylation, thereby disrupting tumor responsiveness to IFN-γ, which leads to a reduction in the expression of downstream chemokines, including CXCL9, CXCL10, and CXCL11, ultimately facilitating immune escape of the tumor. Furthermore, we developed a cell-penetrating peptide, K193-pe, that can competitively inhibit STAT1 K193 lactylation and re-sensitize tumor cells to IFN-γ signaling, thus enhancing CD8+ T cell recruitment and improving the efficacy of immune checkpoint blockade therapy. Collectively, this study elucidates the functional significance of STAT1 K193 lactylation in tumor immunity and suggests that targeted inhibition of this modification, when paired with immunotherapy, may offer a viable treatment strategy.